Methods Of Treating Metabolic Disorders And Cardiovascular Disease With Inhibin Subunit Beta E (INHBE) Inhibitors

ABSTRACT

The present disclosure provides methods of treating a subject having metabolic disorders and/or cardiovascular diseases, methods of identifying subjects having an increased risk of developing a metabolic disorder and/or a cardiovascular disease, and methods of detecting human Inhibin Subunit Beta E variant nucleic acid molecules and variant polypeptides.

REFERENCE TO SEQUENCE LISTING

This application includes a Sequence Listing submitted electronically asa text file named 18923805711SEQ, created on Apr. 1, 2022, with a sizeof 974 kilobytes. The Sequence Listing is incorporated herein byreference.

FIELD

The present disclosure relates generally to the treatment of subjectshaving metabolic disorders and/or cardiovascular disease with InhibinSubunit Beta E inhibitors, methods of identifying subjects having anincreased risk of developing a metabolic disorder and/or cardiovasculardisease, and methods of detecting INHBE variant nucleic acid moleculesand variant polypeptides.

BACKGROUND

Body fat distribution is an important risk factor for cardiovascular andmetabolic disease independent of overall adiposity. A body fatdistribution characterized by higher accumulation of fat around thewaist (such as greater abdominal fat or larger waist circumference)and/or lower accumulation of fat around the hips (such as lowergluteofemoral fat or smaller hip circumference), resulting in a greaterwaist-to-hip ratio (WHR), is associated with higher cardio-metabolicrisk independent of body mass index (BMI). Metabolic conditionsassociated with body fat distribution include, but are not limited to:type 2 diabetes, hyperlipidemia or dyslipidemia (high or alteredcirculating levels of low-density lipoprotein cholesterol (LDL-C),triglycerides, very low-density lipoprotein cholesterol (VLDL-C),apolipoprotein B or other lipid fractions), obesity (particularlyabdominal obesity), lipodystrophy (such as an inability to deposit fatin adipose depots regionally (partial lipodystrophy) or in the wholebody (lipoatrophy)), insulin resistance or higher or altered insulinlevels at fasting or during a metabolic challenge, liver fat depositionor fatty liver disease and their complications (such as, for example,cirrhosis, fibrosis, or inflammation of the liver), nonalcoholicsteatohepatitis, other types of liver inflammation, higher or elevatedor altered liver enzyme levels or other markers of liver damage,inflammation or fat deposition in the liver, higher blood pressureand/or hypertension, higher blood sugar or glucose or hyperglycemia,metabolic syndrome, coronary artery disease, and other atheroscleroticconditions, and the complications of each of the aforementionedconditions. Identifying genetic variants associated with a morefavorable fat distribution (such as a lower WHR, particularly whenadjusted for BMI) can be a pathway to identify mechanisms that can beexploited therapeutically for benefit in these cardio-metabolicdiseases.

Inhibin Subunit Beta E (INHBE) is a member of the TGF-beta (transforminggrowth factor-beta) superfamily of proteins. Inhibins have beenimplicated in regulating numerous cellular processes including cellproliferation, apoptosis, immune response and hormone secretion.Inhibins and activins inhibit and activate, respectively, the secretionof follitropin by the pituitary gland. Inhibins/activins are involved inregulating a number of diverse functions such as hypothalamic andpituitary hormone secretion, gonadal hormone secretion, germ celldevelopment and maturation, erythroid differentiation, insulinsecretion, nerve cell survival, embryonic axial development or bonegrowth, depending on their subunit composition. Inhibins appear tooppose the functions of activins. In addition, INHBE may be upregulatedunder conditions of endoplasmic reticulum stress, and this protein mayinhibit cellular proliferation and growth in pancreas and liver.

SUMMARY

The present disclosure provides methods of treating a subject having ametabolic disorder or at risk of developing a metabolic disorder, themethods comprising administering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving type 2 diabetes or at risk of developing type 2 diabetes, themethods comprising administering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving obesity or at risk of developing obesity, the methods comprisingadministering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving elevated triglyceride level (hypertriglyceridemia) or at risk ofdeveloping elevated triglyceride level (hypertriglyceridemia), themethods comprising administering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving lipodystrophy or at risk of developing lipodystrophy, the methodscomprising administering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving liver inflammation or at risk of developing liver inflammation,the methods comprising administering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving fatty liver disease or at risk of developing fatty liver disease,the methods comprising administering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving hypercholesterolemia or at risk of developinghypercholesterolemia, the methods comprising administering an INHBEinhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving elevated liver enzymes (such as, for example, alaninetransaminase (ALT) and/or aspartate transaminase (AST)) or at risk ofdeveloping elevated liver enzymes (such as, for example, ALT and/orAST), the methods comprising administering an INHBE inhibitor to thesubject.

The present disclosure also provides methods of treating a subjecthaving nonalcoholic steatohepatitis (NASH) or at risk of developingNASH, the methods comprising administering an INHBE inhibitor to thesubject.

The present disclosure also provides methods of treating a subjecthaving a cardiovascular disease or at risk of developing acardiovascular disease, the methods comprising administering an INHBEinhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving cardiomyopathy or at risk of developing cardiomyopathy, themethods comprising administering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving heart failure or at risk of developing heart failure, the methodscomprising administering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving high blood pressure or at risk of developing high blood pressure,the methods comprising administering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subject witha therapeutic agent that treats or inhibits a metabolic disorder,wherein the subject is suffering from a metabolic disorder, the methodscomprise the steps of: determining whether the subject has an INHBEvariant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide by: obtaining or having obtained abiological sample from the subject; and performing or having performed agenotyping assay on the biological sample to determine if the subjecthas a genotype comprising the INHBE variant nucleic acid molecule; andwhen the subject is INHBE reference, then administering or continuing toadminister to the subject the therapeutic agent that treats or inhibitsthe metabolic disorder in a standard dosage amount, and administering tothe subject an INHBE inhibitor; and when the subject is heterozygous foran INHBE variant nucleic acid molecule, then administering or continuingto administer to the subject the therapeutic agent that treats orinhibits the metabolic disorder in an amount that is the same as orlower than a standard dosage amount, and administering to the subject anINHBE inhibitor; when the subject is homozygous for an INHBE variantnucleic acid molecule, then administering or continuing to administer tothe subject the therapeutic agent that treats or inhibits the metabolicdisorder in an amount that is the same as or lower than a standarddosage amount; wherein the presence of a genotype having the INHBEvariant nucleic acid molecule encoding the INHBE predictedloss-of-function polypeptide indicates the subject has a decreased riskof developing the metabolic disorder.

The present disclosure also provides methods of treating a subject witha therapeutic agent that treats or inhibits a cardiovascular disease,wherein the subject is suffering from a cardiovascular disease, themethods comprise the steps of: determining whether the subject has anINHBE variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide by: obtaining or having obtained abiological sample from the subject; and performing or having performed agenotyping assay on the biological sample to determine if the subjecthas a genotype comprising the INHBE variant nucleic acid molecule; andwhen the subject is INHBE reference, then administering or continuing toadminister to the subject the therapeutic agent that treats or inhibitsthe cardiovascular disease in a standard dosage amount, andadministering to the subject an INHBE inhibitor; and when the subject isheterozygous for an INHBE variant nucleic acid molecule, thenadministering or continuing to administer to the subject the therapeuticagent that treats or inhibits the cardiovascular disease in an amountthat is the same as or lower than a standard dosage amount, andadministering to the subject an INHBE inhibitor; when the subject ishomozygous for an INHBE variant nucleic acid molecule, thenadministering or continuing to administer to the subject the therapeuticagent that treats or inhibits the cardiovascular disease in an amountthat is the same as or lower than a standard dosage amount; wherein thepresence of a genotype having the INHBE variant nucleic acid moleculeencoding the INHBE predicted loss-of-function polypeptide indicates thesubject has a decreased risk of developing the cardiovascular disease.

The present disclosure also provides methods of identifying a subjecthaving an increased risk for developing a metabolic disorder, whereinthe methods comprise: determining or having determined the presence orabsence of an INHBE variant nucleic acid molecule encoding an INHBEpredicted loss-of-function polypeptide in a biological sample obtainedfrom the subject; wherein: when the subject is INHBE reference, then thesubject has an increased risk for developing the metabolic disorder; andwhen the subject is heterozygous for an INHBE variant nucleic acidmolecule or homozygous for an INHBE variant nucleic acid molecule, thenthe subject has a decreased risk for developing the metabolic disorder.

The present disclosure also provides methods of identifying a subjecthaving an increased risk for developing a cardiovascular disease,wherein the methods comprise: determining or having determined thepresence or absence of an INHBE variant nucleic acid molecule encodingan INHBE predicted loss-of-function polypeptide in a biological sampleobtained from the subject; wherein: when the subject is INHBE reference,then the subject has an increased risk for developing the cardiovasculardisease; and when the subject is heterozygous for an INHBE variantnucleic acid molecule or homozygous for an INHBE variant nucleic acidmolecule, then the subject has a decreased risk for developing thecardiovascular disease.

The present disclosure also provides therapeutic agents that treat orinhibit a metabolic disorder for use in the treatment of the metabolicdisorder in a subject having: an INHBE variant genomic nucleic acidmolecule encoding an INHBE predicted loss-of-function polypeptide; anINHBE variant mRNA molecule encoding an INHBE predicted loss-of-functionpolypeptide; or an INHBE variant cDNA molecule encoding an INHBEpredicted loss-of-function polypeptide.

The present disclosure also provides therapeutic agents that treat orinhibit a cardiovascular disease for use in the treatment of thecardiovascular disease in a subject having: an INHBE variant genomicnucleic acid molecule encoding an INHBE predicted loss-of-functionpolypeptide; an INHBE variant mRNA molecule encoding an INHBE predictedloss-of-function polypeptide; or an INHBE variant cDNA molecule encodingan INHBE predicted loss-of-function polypeptide.

The present disclosure also provides INHBE inhibitors that treat orinhibit a metabolic disorder for use in the treatment of the metabolicdisorder in a subject having: an INHBE variant genomic nucleic acidmolecule encoding an INHBE predicted loss-of-function polypeptide; anINHBE variant mRNA molecule encoding an INHBE predicted loss-of-functionpolypeptide; or an INHBE variant cDNA molecule encoding an INHBEpredicted loss-of-function polypeptide.

The present disclosure also provides INHBE inhibitors that treat orinhibit a cardiovascular disease for use in the treatment of thecardiovascular disease in a subject having: an INHBE variant genomicnucleic acid molecule encoding an INHBE predicted loss-of-functionpolypeptide; an INHBE variant mRNA molecule encoding an INHBE predictedloss-of-function polypeptide; or an INHBE variant cDNA molecule encodingan INHBE predicted loss-of-function polypeptide.

BRIEF DESCRIPTION OF THE FIGURES

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

The accompanying figures, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the presentdisclosure.

FIG. 1 shows association of INHBE predicted loss-of-function (pLOF)variants with a favorable fat distribution (i.e., lower BMI adjustedWHR) in an exome sequencing analysis of over 525,000 people frommultiple studies; association analyses were estimated by fittingmixed-effects linear regression models accounting for relatedness andpopulation stratification using the REGENIE software; abbreviations:confidence interval, CI; standard deviation, SD; body mass index, BMI;waist-hip ratio adjusted for BMI, WHRadjBMI; reference-reference allele,RR; reference-alternative allele, RA; alternative-alternative allele,AA; UK Biobank cohort, UKB; European ancestry, EUR; Mexico cityprospective study cohort, MCPS; predicted loss-of-function, pLOF.

FIG. 2 depicts a gene model for INHBE showing the location of pLOFvariants (top panel) and the phenotypic distribution of BMI-adjusted WHRin carriers of each variant; the blue bar shows the median BMI-adjustedWHR in non-carriers, while the red bar shows the median BMI-adjusted WHRin carriers; two variants highlighted in dark red were individuallyassociated with lower BMI-adjusted WHR; data are from the UK Biobank(UKB) and Mexico City Prospective Study (MCPS) cohorts; abbreviations:body mass index, BMI; waist-hip ratio, WHR.

FIG. 3 shows the in silico predicted functional consequences of theINHBE c.299-1G:C (12:57456093:G:C) splice variant; top sequence=originalexon 2 (SEQ ID NO:28); bottom sequence=predicted exon 2 (SEQ ID NO:29).

FIG. 4 shows the wild type INHBE protein sequence (top; SEQ ID NO:8) andthe in silico predicted protein sequence for the c.299-1G:C acceptorsplice variant (bottom; SEQ ID NO:8 showing change in non-highlightedregion).

FIG. 5 shows Chinese hamster ovary (CHO) cells experiments for thec.299-1G>C: variant. The variant occurs in the splice acceptor site forthe first and only splice junction in the INHBE gene (Panel A). In CHOcells, the c.299-1G>C variant results in the expression of a lowermolecular weight variant which is present in cell lysates but not in themedia, consistent with a loss-of-function (Panel B).

FIG. 6 shows associations of INHBE pLOF variants with body fat and leanmass, percentage and body-surface adjusted indices as measured byelectrical bioimpedance in 423,418 participants from the UKB study.

FIG. 7 shows INHBE expression patterns across tissues (left) and livercell-types (right). The first panel shows, per tissue, the normalizedmRNA expression values for INHBE in counts per million (CPM) using datafrom genotype tissue expression (GTEx) consortium (GTEx Portal 2021.Accessed 2021, June 1^(st) via world wide web at “gtexportal.org/”). Thesecond panel shows normalized cell-type specific expression levelswithin liver, in transcripts per million protein coding genes (pTPM),obtained from the human protein atlas (HPA) (Uhlen et al., Nat.Biotechnol. 2010, 28, 1248-50). Box plots depict the median (thick blackvertical bar), the interquartile range, and minimum and maximum CPMvalues across individuals per tissue.

FIG. 8 shows liver mRNA expression of INHBE is upregulated in patientswith steatosis and nonalcoholic steatohepatitis (NASH) compared toindividuals with normal liver in bariatric surgery patients from GHS. Inthe top panel, the Figure shows liver mRNA expression levels of INHBE intranscripts per million (TPM; a normalization of RNA molecules for every1 million molecules detected in a certain experiment) in patients withnormal liver (control), steatosis of the liver (simple steatosis) andnonalcoholic steatohepatitis (NASH). In the bottom panel are statisticsfor comparisons between groups. The simple steatosis group showed higherexpression of INHBE in the liver than the control group. The NASH groupshowed higher expression both when compared to the control and whencompared to the simple steatosis groups. All differences in expressionbetween groups were statistically significant.

DESCRIPTION

Various terms relating to aspects of the present disclosure are usedthroughout the specification and claims. Such terms are to be giventheir ordinary meaning in the art, unless otherwise indicated. Otherspecifically defined terms are to be construed in a manner consistentwith the definitions provided herein.

Unless otherwise expressly stated, it is in no way intended that anymethod or aspect set forth herein be construed as requiring that itssteps be performed in a specific order. Accordingly, where a methodclaim does not specifically state in the claims or descriptions that thesteps are to be limited to a specific order, it is in no way intendedthat an order be inferred, in any respect. This holds for any possiblenon-expressed basis for interpretation, including matters of logic withrespect to arrangement of steps or operational flow, plain meaningderived from grammatical organization or punctuation, or the number ortype of aspects described in the specification.

As used herein, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise.

As used herein, the term “about” means that the recited numerical valueis approximate and small variations would not significantly affect thepractice of the disclosed embodiments. Where a numerical value is used,unless indicated otherwise by the context, the term “about” means thenumerical value can vary by ±10% and remain within the scope of thedisclosed embodiments.

As used herein, the term “comprising” may be replaced with “consisting”or “consisting essentially of” in particular embodiments as desired.

As used herein, the term “isolated”, in regard to a nucleic acidmolecule or a polypeptide, means that the nucleic acid molecule orpolypeptide is in a condition other than its native environment, such asapart from blood and/or animal tissue. In some embodiments, an isolatednucleic acid molecule or polypeptide is substantially free of othernucleic acid molecules or other polypeptides, particularly other nucleicacid molecules or polypeptides of animal origin. In some embodiments,the nucleic acid molecule or polypeptide can be in a highly purifiedform, i.e., greater than 95% pure or greater than 99% pure. When used inthis context, the term “isolated” does not exclude the presence of thesame nucleic acid molecule or polypeptide in alternative physical forms,such as dimers or Alternately phosphorylated or derivatized forms.

As used herein, the terms “nucleic acid”, “nucleic acid molecule”,“nucleic acid sequence”, “polynucleotide”, or “oligonucleotide” cancomprise a polymeric form of nucleotides of any length, can comprise DNAand/or RNA, and can be single-stranded, double-stranded, or multiplestranded. One strand of a nucleic acid also refers to its complement.

As used herein, the term “subject” includes any animal, includingmammals. Mammals include, but are not limited to, farm animals (such as,for example, horse, cow, pig), companion animals (such as, for example,dog, cat), laboratory animals (such as, for example, mouse, rat,rabbits), and non-human primates. In some embodiments, the subject is ahuman. In some embodiments, the human is a patient under the care of aphysician.

It has been observed in accordance with the present disclosure thatloss-of-function variants in INHBE (whether these variations arehomozygous or heterozygous in a particular subject) associate with adecreased risk of developing a metabolic disorder, such as type 2diabetes, obesity, lipodystrophy, liver inflammation, fatty liverdisease, hypercholesterolemia, elevated liver enzymes (such as, forexample, ALT and/or AST), NASH, and/or elevated triglyceride level,and/or a cardiovascular disease, such as cardiomyopathy, heart failure,and high blood pressure. It is believed that loss-of-function variantsin the INHBE gene or protein have not been associated with metabolicdisorders and/or cardiovascular disease in genome-wide or exome-wideassociation studies. Therefore, subjects that are homozygous orheterozygous for reference INHBE variant nucleic acid molecules may betreated with an INHBE inhibitor such that a metabolic disorder and/orcardiovascular disease is inhibited, the symptoms thereof are reduced,and/or development of symptoms is repressed. It is also believed thatsuch subjects having metabolic disorders and/or cardiovascular diseasemay further be treated with therapeutic agents that treat or inhibit ametabolic disorder, such as type 2 diabetes, obesity, high bloodpressure, lipodystrophy, liver inflammation, fatty liver disease,hypercholesterolemia, elevated liver enzymes (such as, for example, ALTand/or AST), NASH, and/or elevated triglyceride level, and/orcardiovascular disease such as cardiomyopathy, heart failure, and highblood pressure.

For purposes of the present disclosure, any particular subject, such asa human, can be categorized as having one of three INHBE genotypes: i)INHBE reference; ii) heterozygous for an INHBE variant nucleic acidmolecule encoding an INHBE predicted loss-of-function polypeptide; oriii) homozygous for an INHBE variant nucleic acid molecule encoding anINHBE predicted loss-of-function polypeptide. A subject is INHBEreference when the subject does not have a copy of an INHBE variantnucleic acid molecule encoding an INHBE predicted loss-of-functionpolypeptide. A subject is heterozygous for an INHBE variant nucleic acidmolecule when the subject has a single copy of an INHBE variant nucleicacid molecule encoding an INHBE predicted loss-of-function polypeptide.An INHBE variant nucleic acid molecule is any nucleic acid molecule(such as, a genomic nucleic acid molecule, an mRNA molecule, or a cDNAmolecule) encoding an INHBE polypeptide having a partialloss-of-function, a complete loss-of-function, a predicted partialloss-of-function, or a predicted complete loss-of-function. A subjectwho has an INHBE polypeptide having a partial loss-of-function (orpredicted partial loss-of-function) is hypomorphic for INHBE. A subjectis homozygous for an INHBE variant nucleic acid molecule encoding anINHBE predicted loss-of-function polypeptide when the subject has twocopies (same or different) of an INHBE variant nucleic acid moleculeencoding an INHBE predicted loss-of-function polypeptide.

For subjects that are genotyped or determined to be INHBE reference,such subjects have an increased risk of developing a metabolic disorder,such as type 2 diabetes, lipodystrophy, liver inflammation, fatty liverdisease, hypercholesterolemia, elevated liver enzymes (such as, forexample, ALT and/or AST), obesity, high blood pressure, and/or elevatedtriglyceride level (hypertriglyceridemia), and/or a cardiovasculardisease, such as cardiomyopathy, heart failure, and high blood pressure.For subjects that are genotyped or determined to be either INHBEreference or heterozygous for an INHBE variant nucleic acid molecule,such subjects or subjects can be treated with an INHBE inhibitor.

In any of the embodiments described herein, the INHBE variant nucleicacid molecule can be any nucleic acid molecule (such as, for example,genomic nucleic acid molecule, mRNA molecule, or cDNA molecule) encodingan INHBE polypeptide having a partial loss-of-function, a completeloss-of-function, a predicted partial loss-of-function, or a predictedcomplete loss-of-function. In some embodiments, the INHBE variantnucleic acid molecule is associated with a reduced in vitro response toINHBE ligands compared with reference INHBE. In some embodiments, theINHBE variant nucleic acid molecule is an INHBE variant that results oris predicted to result in a premature truncation of an INHBE polypeptidecompared to the human reference genome sequence. In some embodiments,the INHBE variant nucleic acid molecule is a variant that is predictedto be damaging by in vitro prediction algorithms such as Polyphen, SIFT,or similar algorithms. In some embodiments, the INHBE variant nucleicacid molecule is a variant that causes or is predicted to cause anonsynonymous amino-acid substitution in INHBE and whose allelefrequency is less than 1/100 alleles in the population from which thesubject is selected. In some embodiments, the INHBE variant nucleic acidmolecule is any rare missense variant (allele frequency <0.1%; or 1 in1,000 alleles), or any splice-site, stop-gain, start-loss, stop-loss,frameshift, or in-frame indel, or other frameshift INHBE variant.

In any of the embodiments described herein, the INHBE predictedloss-of-function polypeptide can be any INHBE polypeptide having apartial loss-of-function, a complete loss-of-function, a predictedpartial loss-of-function, or a predicted complete loss-of-function.

In any of the embodiments described herein, the INHBE variant nucleicacid molecules encoding variations in the protein sequence can includevariations at positions of chromosome 12 using the nucleotide sequenceof the INHBE reference genomic nucleic acid molecule (SEQ ID NO:1;ENST00000266646.3 chr12:57455307-57458025 in the GRCh38/hg38 humangenome assembly) as a reference sequence.

Numerous genetic variants in INHBE exist which cause subsequent changesin the INHBE polypeptide sequence including, but not limited to: Gln7fs,Arg18STOP, Gln37STOP, Arg40STOP, Leu55fs, Cys139fs, Arg144STOP,Cys192fs, Arg224fs, Arg224STOP, Arg233fs, Arg250STOP, Asp251fs,Tyr253STOP, Tyr275STOP, Ser293fs, Trp308fs, Pro309fs, Arg320STOP,Leu323fs, and Ter351Tyrext*?. Additional variant genomic nucleic acidmolecules of INHBE exist, including, but not limited to (using the humangenome reference build GRch38): C298+1G:T (12:57455835:G:T), c.299-2A:G,c.299-1G:C (12:57456093:G:C), and 12:57259799:A:C. Additional variantINHBE polypeptides exist, including, but not limited to INHBEpolypeptide having the methionine at position 1 removed.

Any one or more (i.e., any combination) of the INHBE pLOF variants canbe used within any of the methods described herein to determine whethera subject has an increased risk for developing a metabolic disorderand/or a cardiovascular disease. The combinations of particular variantscan form a mask used for statistical analysis of the particularcorrelation of INHBE and increased type 2 diabetes/BMI risk and/or acardiovascular disease.

In any of the embodiments described herein, the metabolic disorder istype 2 diabetes, obesity, NASH, and/or elevated triglyceride level. Inany of the embodiments described herein, the metabolic disorder is type2 diabetes. In any of the embodiments described herein, the metabolicdisorder is obesity. In any of the embodiments described herein, themetabolic disorder is NASH. In any of the embodiments described herein,the metabolic disorder is elevated triglyceride level. In any of theembodiments described herein, the metabolic disorder is lipodystrophy.In any of the embodiments described herein, the metabolic disorder isliver inflammation. In any of the embodiments described herein, themetabolic disorder is fatty liver disease. In any of the embodimentsdescribed herein, the metabolic disorder is hypercholesterolemia. In anyof the embodiments described herein, the metabolic disorder is elevatedliver enzymes (such as, for example, ALT and/or AST).

Metabolic disorders/conditions associated with body fat distributionalso include, but are not limited to: type 2 diabetes, hyperlipidemia ordyslipidemia (high or altered circulating levels of low-densitylipoprotein cholesterol (LDL-C), triglycerides, very low-densitylipoprotein cholesterol (VLDL-C), apolipoprotein B or other lipidfractions), obesity (particularly abdominal obesity), lipodystrophy(such as an inability to deposit fat in adipose depots regionally(partial lipodystrophy) or in the whole body (lipoatrophy)), insulinresistance or higher or altered insulin levels at fasting or during aglucose or insulin challenge, liver fat deposition or fatty liverdisease and their complications (such as, for example, cirrhosis,fibrosis, or inflammation of the liver), higher or elevated or alteredliver enzyme levels or other markers of liver damage, inflammation orfat deposition, higher blood pressure and/or hypertension, higher bloodsugar or glucose or hyperglycemia, metabolic syndrome, coronary arterydisease, and other atherosclerotic conditions, and the complications ofeach of the aforementioned conditions.

In any of the embodiments described herein, the cardiovascular diseaseis cardiomyopathy, heart failure, or high blood pressure. In any of theembodiments described herein, the cardiovascular disease iscardiomyopathy. In any of the embodiments described herein, thecardiovascular disease is heart failure. In any of the embodimentsdescribed herein, the cardiovascular disease is high blood pressure.

The present disclosure provides methods of treating a subject having orat risk of developing a metabolic disorder, the methods comprisingadministering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving or at risk of developing type 2 diabetes, the methods comprisingadministering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving or at risk of developing obesity, the methods comprisingadministering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving or at risk of developing elevated triglyceride level, the methodscomprising administering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving or at risk of developing NASH, the methods comprisingadministering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving or at risk of developing lipodystrophy, the methods comprisingadministering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving or at risk of developing liver inflammation, the methodscomprising administering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving or at risk of developing fatty liver disease, the methodscomprising administering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving or at risk of developing hypercholesterolemia, the methodscomprising administering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving or at risk of developing elevated liver enzymes (such as, forexample, ALT and/or AST), the methods comprising administering an INHBEinhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving or at risk of developing a cardiovascular disease, the methodscomprising administering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving or at risk of developing cardiomyopathy, the methods comprisingadministering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving or at risk of developing heart failure, the methods comprisingadministering an INHBE inhibitor to the subject.

The present disclosure also provides methods of treating a subjecthaving or at risk of developing high blood pressure, the methodscomprising administering an INHBE inhibitor to the subject.

In some embodiments, the INHBE inhibitor comprises an inhibitory nucleicacid molecule. Examples of inhibitory nucleic acid molecules include,but are not limited to, antisense nucleic acid molecules, smallinterfering RNAs (siRNAs), and short hairpin RNAs (shRNAs). Suchinhibitory nucleic acid molecules can be designed to target any regionof an INHBE mRNA. In some embodiments, the antisense RNA, siRNA, orshRNA hybridizes to a sequence within an INHBE genomic nucleic acidmolecule or mRNA molecule and decreases expression of the INHBEpolypeptide in a cell in the subject. In some embodiments, the INHBEinhibitor comprises an antisense RNA that hybridizes to an INHBE genomicnucleic acid molecule or mRNA molecule and decreases expression of theINHBE polypeptide in a cell in the subject. In some embodiments, theINHBE inhibitor comprises an siRNA that hybridizes to an INHBE genomicnucleic acid molecule or mRNA molecule and decreases expression of theINHBE polypeptide in a cell in the subject. In some embodiments, theINHBE inhibitor comprises an shRNA that hybridizes to an INHBE genomicnucleic acid molecule or mRNA molecule and decreases expression of theINHBE polypeptide in a cell in the subject.

In some embodiments, the antisense nucleic acid molecules comprise orconsist of the nucleotide sequences shown in Table 1.

TABLE 1 SEQ ID Sequence NO: ACAGCUCAUGUCUGGCUACU 30 UGACCCUCACAGCUCAUGUC31 UUGACCCUCACAGCUCAUGU 32 UGCUUGACCCUCACAGCUCA 33 GUGCUUGACCCUCACAGCUC34 UAGCUGUGCUUGACCCUCAC 35 AUAGCUGUGCUUGACCCUCA 36 GAUAGCUGUGCUUGACCCUC37 GGAUAGCUGUGCUUGACCCU 38 UGGAUAGCUGUGCUUGACCC 39 AUGGAUAGCUGUGCUUGACC40 GAUGGAUAGCUGUGCUUGAC 41 UGAUGGAUAGCUGUGCUUGA 42 AUCUGAUGGAUAGCUGUGCU43 CAUCUGAUGGAUAGCUGUGC 44 AUCAUCUGAUGGAUAGCUGU 45 GAUCAUCUGAUGGAUAGCUG46 AGAUCAUCUGAUGGAUAGCU 47 UAGAUCAUCUGAUGGAUAGC 48 GUAGAUCAUCUGAUGGAUAG49 GAAAGUAGAUCAUCUGAUGG 50 GCUGAAAGUAGAUCAUCUGA 51 AGGCUGAAAGUAGAUCAUCU52 AAGGCUGAAAGUAGAUCAUC 53 GAAGGCUGAAAGUAGAUCAU 54 GGAAGGCUGAAAGUAGAUCA55 AGGAAGGCUGAAAGUAGAUC 56 GUCUGGGACUCAGGAAGGCU 57 UAUUGUCUGGGACUCAGGAA58 CUAUUGUCUGGGACUCAGGA 59 UCUAUUGUCUGGGACUCAGG 60 CUUCUAUUGUCUGGGACUCA61 UCUUCUAUUGUCUGGGACUC 62 CACCUGUCUUCUAUUGUCUG 63 CCACCUGUCUUCUAUUGUCU64 GCCACCUGUCUUCUAUUGUC 65 AGCCACCUGUCUUCUAUUGU 66 AUGAGGGCACAGUGACAGCA67 CAAUGAGGGCACAGUGACAG 68 CCAAUGAGGGCACAGUGACA 69 CGUCUGUUGAGUCUGAUUGC70 CCGUCUGUUGAGUCUGAUUG 71 UCCGUCUGUUGAGUCUGAUU 72 CUCCGUCUGUUGAGUCUGAU73 GCUCCGUCUGUUGAGUCUGA 74 UGCUCCGUCUGUUGAGUCUG 75 UUGCUCCGUCUGUUGAGUCU76 AGUUGCUCCGUCUGUUGAGU 77 GCAGUUGCUCCGUCUGUUGA 78 GGCAGUUGCUCCGUCUGUUG79 GAUGGCAGUUGCUCCGUCUG 80 GGAUGGCAGUUGCUCCGUCU 81 AGCCUCGGAUGGCAGUUGCU82 AGGAGCCUCGGAUGGCAGUU 83 UUCAGGAGCCUCGGAUGGCA 84 UGGUUCAGGAGCCUCGGAUG85 CUGGUUCAGGAGCCUCGGAU 86 CUGGUGAAUGGCCCUGGUUC 87 CCUGGUGAAUGGCCCUGGUU88 UCCUGGUGAAUGGCCCUGGU 89 UGGACAUCAGGGAGCCGCAU 90 AGGAUUUGCUGCUUGGCUAG91 CAGGAUUUGCUGCUUGGCUA 92 UCCAGGAUUUGCUGCUUGGC 93 ACCCAUCCAGGAUUUGCUGC94 AACCCAUCCAGGAUUUGCUG 95 CAACCCAUCCAGGAUUUGCU 96 UGCAACCCAUCCAGGAUUUG97 GUGCAACCCAUCCAGGAUUU 98 GGUGCAACCCAUCCAGGAUU 99 AGGUGCAACCCAUCCAGGAU100 CAGGUGCAACCCAUCCAGGA 101 UCAGGUGCAACCCAUCCAGG 102GUCAGGUGCAACCCAUCCAG 103 GGUCAGGUGCAACCCAUCCA 104 UGGUCAGGUGCAACCCAUCC105 CUGGUCAGGUGCAACCCAUC 106 ACUGGUCAGGUGCAACCCAU 107GACUGGUCAGGUGCAACCCA 108 ACGACUGGUCAGGUGCAACC 109 GACGACUGGUCAGGUGCAAC110 GGACGACUGGUCAGGUGCAA 111 UCUGGGACGACUGGUCAGGU 112UUCUGGGACGACUGGUCAGG 113 AUUCUGGGACGACUGGUCAG 114 UAUUCUGGGACGACUGGUCA115 UUAUUCUGGGACGACUGGUC 116 GUUAUUCUGGGACGACUGGU 117AGUUAUUCUGGGACGACUGG 118 GAGUUAUUCUGGGACGACUG 119 UGAGUUAUUCUGGGACGACU120 AUGAGUUAUUCUGGGACGAC 121 GAUGAGUUAUUCUGGGACGA 122GGAUGAGUUAUUCUGGGACG 123 UGGAGGAUGAGUUAUUCUGG 124 GUGGAGGAUGAGUUAUUCUG125 GGUGGAGGAUGAGUUAUUCU 126 GGGUGGAGGAUGAGUUAUUC 127AAAGCUGAUGACCUCCUCCC 128 CAAAGCUGAUGACCUCCUCC 129 AGCAAAGCUGAUGACCUCCU130 UAGCAAAGCUGAUGACCUCC 131 GUAGCAAAGCUGAUGACCUC 132AGUAGCAAAGCUGAUGACCU 133 ACAGUAGCAAAGCUGAUGAC 134 UGACAGUAGCAAAGCUGAUG135 GUGACAGUAGCAAAGCUGAU 136 GUCUGUGACAGUAGCAAAGC 137AGUCUGUGACAGUAGCAAAG 138 GAGUCUGUGACAGUAGCAAA 139 UGGAGUCUGUGACAGUAGCA140 GUGGAGUCUGUGACAGUAGC 141 AGUGGAGUCUGUGACAGUAG 142AAGUGGAGUCUGUGACAGUA 143 UGAAGUGGAGUCUGUGACAG 144 CUGAAGUGGAGUCUGUGACA145 GCUGAAGUGGAGUCUGUGAC 146 GGCUGAAGUGGAGUCUGUGA 147AGGCUGAAGUGGAGUCUGUG 148 UAGGCUGAAGUGGAGUCUGU 149 GUAGGCUGAAGUGGAGUCUG150 GCUGUAGGCUGAAGUGGAGU 151 AGCUGUAGGCUGAAGUGGAG 152GAGCUGUAGGCUGAAGUGGA 153 GGGAGCUGUAGGCUGAAGUG 154 AGGGAGCUGUAGGCUGAAGU155 AAGUGAGCAGGGAGCUGUAG 156 UGGACAGGUGAAAAGUGAGC 157GUGGACAGGUGAAAAGUGAG 158 AGUGGACAGGUGAAAAGUGA 159 GAGUGGACAGGUGAAAAGUG160 GGAGUGGACAGGUGAAAAGU 161 AGGAGUGGACAGGUGAAAAG 162GAGGAGUGGACAGGUGAAAA 163 CGAGGAGUGGACAGGUGAAA 164 CCGAGGAGUGGACAGGUGAA165 ACCGAGGAGUGGACAGGUGA 166 CAUGGUACAGGUGGUGGGAC 167GCAUGGUACAGGUGGUGGGA 168 CAAAGAGUGCCAGGAAGGGU 169 GCAAAGAGUGCCAGGAAGGG170 AAGCAAAGAGUGCCAGGAAG 171 UCAAGCAAAGAGUGCCAGGA 172CUCAAGCAAAGAGUGCCAGG 173 CCUCAAGCAAAGAGUGCCAG 174 AUCCUCAAGCAAAGAGUGCC175 GAUCCUCAAGCAAAGAGUGC 176 GAAGAUCCUCAAGCAAAGAG 177GGAAGAUCCUCAAGCAAAGA 178 CGGAAGAUCCUCAAGCAAAG 179 AUCGGAAGAUCCUCAAGCAA180 CAUCGGAAGAUCCUCAAGCA 181 CCAUCGGAAGAUCCUCAAGC 182CCCAUCGGAAGAUCCUCAAG 183 AUGUGGUGCUCAGCCAGGAG 184 UUGGUGAUGUGGUGCUCAGC185 GGUUGGUGAUGUGGUGCUCA 186 AGGUUGGUGAUGUGGUGCUC 187CAGGUUGGUGAUGUGGUGCU 188 AGCCCAGGUUGGUGAUGUGG 189 CAGCCCAGGUUGGUGAUGUG190 UGCCAGCCCAGGUUGGUGAU 191 AUGCCAGCCCAGGUUGGUGA 192GUAUGCCAGCCCAGGUUGGU 193 AGGUAUGCCAGCCCAGGUUG 194 AAGGUAUGCCAGCCCAGGUU195 UAAGGUAUGCCAGCCCAGGU 196 UUAAGGUAUGCCAGCCCAGG 197GUUAAGGUAUGCCAGCCCAG 198 AGUUAAGGUAUGCCAGCCCA 199 GAGUUAAGGUAUGCCAGCCC200 AGAGUUAAGGUAUGCCAGCC 201 CAGAGUUAAGGUAUGCCAGC 202GCAGAGUUAAGGUAUGCCAG 203 AGGGCAGAGUUAAGGUAUGC 204 AGAGGGCAGAGUUAAGGUAU205 UAGAGGGCAGAGUUAAGGUA 206 CUAGAGGGCAGAGUUAAGGU 207CACUAGAGGGCAGAGUUAAG 208 GCCACUAGAGGGCAGAGUUA 209 GGACACCAGACUUCUCACCC210 AGGACACCAGACUUCUCACC 211 CAGGACACCAGACUUCUCAC 212UUUCAGGACACCAGACUUCU 213 GUUUCAGGACACCAGACUUC 214 UAGUUGCAGUUUCAGGACAC215 CUAGUUGCAGUUUCAGGACA 216 UCUAGUUGCAGUUUCAGGAC 217GUCUAGUUGCAGUUUCAGGA 218 AGUCUAGUUGCAGUUUCAGG 219 CAGUCUAGUUGCAGUUUCAG220 AACUGUGCUGUUGCCUUCUA 221 UAACUGUGCUGUUGCCUUCU 222GUAACUGUGCUGUUGCCUUC 223 CCAGUAACUGUGCUGUUGCC 224 GUCCAGUAACUGUGCUGUUG225 UGUCCAGUAACUGUGCUGUU 226 UUGUCCAGUAACUGUGCUGU 227GGUUGUCCAGUAACUGUGCU 228 CGGUUGUCCAGUAACUGUGC 229 UCGGUUGUCCAGUAACUGUG230 CUCGGUUGUCCAGUAACUGU 231 CCUCGGUUGUCCAGUAACUG 232GCCUCGGUUGUCCAGUAACU 233 CGCCUCGGUUGUCCAGUAAC 234 CCGCCUCGGUUGUCCAGUAA235 UGCUGGUGUCCUGCUGUGUC 236 CUGCUGGUGUCCUGCUGUGU 237UCUAGGAAGGGCUGCUGGUG 238 UUAAGCUCUAGGAAGGGCUG 239 CUCAUUGGCUCGGAUCUUAA240 GCUCAUUGGCUCGGAUCUUA 241 GGCUCAUUGGCUCGGAUCUU 242AGGCUCAUUGGCUCGGAUCU 243 CAGGCUCAUUGGCUCGGAUC 244 UCCAGGCUCAUUGGCUCGGA245 UCUCGCCUGCAACAUAAGGG 246 CAGAAUGGAAAGAGGCAGCA 247GCAGAAUGGAAAGAGGCAGC 248 AAGACGGCAGAAUGGAAAGA 249 GAAGACGGCAGAAUGGAAAG250 UGAAGACGGCAGAAUGGAAA 251 CUGAAGACGGCAGAAUGGAA 252GCUGAAGACGGCAGAAUGGA 253 GGCUGAAGACGGCAGAAUGG 254 AGGCUGAAGACGGCAGAAUG255 GGAGGCUGAAGACGGCAGAA 256 AGGAGGCUGAAGACGGCAGA 257UGUUGGCUUUGAGGAGGCUG 258 CAAGGAUUGUUGGCUUUGAG 259 UGGCAGGCCAAGGAUUGUUG260 CUGGCAGGCCAAGGAUUGUU 261 ACUGGCAGGCCAAGGAUUGU 262AGGAGGUACUGGCAGGCCAA 263 AACAGGAGGUACUGGCAGGC 264 CAACAGGAGGUACUGGCAGG265 ACACAACAGGAGGUACUGGC 266 AGGGACACAACAGGAGGUAC 267UCGGGCAGUAGGGACACAAC 268 UUCGGGCAGUAGGGACACAA 269 CUUCGGGCAGUAGGGACACA270 AUGAUCCAGGUAGAGGAGAG 271 UAUGAUCCAGGUAGAGGAGA 272UUAUGAUCCAGGUAGAGGAG 273 AUUAUGAUCCAGGUAGAGGA 274 CAUUAUGAUCCAGGUAGAGG275 CCAUUAUGAUCCAGGUAGAG 276 UGCCAUUAUGAUCCAGGUAG 277UUGCCAUUAUGAUCCAGGUA 278 AUUGCCAUUAUGAUCCAGGU 279 CAUUGCCAUUAUGAUCCAGG280 ACAUUGCCAUUAUGAUCCAG 281 CCACAUUGCCAUUAUGAUCC 282GACCACAUUGCCAUUAUGAU 283 UGACCACAUUGCCAUUAUGA 284 UUGACCACAUUGCCAUUAUG285 UCUUGACCACAUUGCCAUUA 286 GUCUUGACCACAUUGCCAUU 287CGUCUUGACCACAUUGCCAU 288 CCGUCUUGACCACAUUGCCA 289 UCCGUCUUGACCACAUUGCC290 AUCCGUCUUGACCACAUUGC 291 CAUCCGUCUUGACCACAUUG 292ACAUCCGUCUUGACCACAUU 293 CACAUCCGUCUUGACCACAU 294 GCACAUCCGUCUUGACCACA295 GGCACAUCCGUCUUGACCAC 296 UGGCACAUCCGUCUUGACCA 297CUGGCACAUCCGUCUUGACC 298 UCUGGCACAUCCGUCUUGAC 299 AUCUGGCACAUCCGUCUUGA300 UAUCUGGCACAUCCGUCUUG 301 AUAUCUGGCACAUCCGUCUU 302CAUAUCUGGCACAUCCGUCU 303 CCAUAUCUGGCACAUCCGUC 304 CACCAUAUCUGGCACAUCCG305 CUCCACCACCAUAUCUGGCA 306 UGGUCUCUUCACUCCAAAGC 307CUUCAUCUUGGUCUCUUCAC 308 ACUUCAUCUUGGUCUCUUCA 309 AACUUCAUCUUGGUCUCUUC310 GGAAACUUCAUCUUGGUCUC 311 CCUCCAGUCACAGAUGCCCU 312GAUGCCUCCAGUCACAGAUG 313 UGAUGCCUCCAGUCACAGAU 314 CAGGUGGUUGUUGGGUUGGG315 CCAGGUGGUUGUUGGGUUGG 316 GCCAGGUGGUUGUUGGGUUG 317UGCCAGGUGGUUGUUGGGUU 318 CAUAUUGCCAGGUGGUUGUU 319 UCAUAUUGCCAGGUGGUUGU320 GUCAUAUUGCCAGGUGGUUG 321 AGUCAUAUUGCCAGGUGGUU 322GAGUCAUAUUGCCAGGUGGU 323 AGUGAGUCAUAUUGCCAGGU 324 AAGUGAGUCAUAUUGCCAGG325 CAAGUGAGUCAUAUUGCCAG 326 GUCAAGUGAGUCAUAUUGCC 327GGUCAAGUGAGUCAUAUUGC 328 GGGUCAAGUGAGUCAUAUUG 329 CCCAUUUGGGUCCCAUAGGG330 GCCCAUUUGGGUCCCAUAGG 331 UGCCCAUUUGGGUCCCAUAG 332GUGCCCAUUUGGGUCCCAUA 333 AGUGCCCAUUUGGGUCCCAU 334 AAGUGCCCAUUUGGGUCCCA335 AAAGUGCCCAUUUGGGUCCC 336 GAAAGUGCCCAUUUGGGUCC 337AGAAAGUGCCCAUUUGGGUC 338 CAAGAAAGUGCCCAUUUGGG 339 ACAAGAAAGUGCCCAUUUGG340 GACAAGAAAGUGCCCAUUUG 341 GAGUCUCAGACAAGAAAGUG 342CCAGAGUCUCAGACAAGAAA 343 GCCAGAGUCUCAGACAAGAA 344 AGCCAGAGUCUCAGACAAGA345 UAAGCCAGAGUCUCAGACAA 346 AUAAGCCAGAGUCUCAGACA 347AGCCAACCUGGAAUAAGCCA 348 UCAGCCAACCUGGAAUAAGC 349 CAUCAGCCAACCUGGAAUAA350 CACAUCAGCCAACCUGGAAU 351 ACACAUCAGCCAACCUGGAA 352AACACAUCAGCCAACCUGGA 353 CAACACAUCAGCCAACCUGG 354 CUCCCAACACAUCAGCCAAC355 CGCUUUACCCAUCUCCCAAC 356 AACGCUUUACCCAUCUCCCA 357AAACGCUUUACCCAUCUCCC 358 AGAAACGCUUUACCCAUCUC 359 AAGAAACGCUUUACCCAUCU360 GAAGAAACGCUUUACCCAUC 361 AGAAGAAACGCUUUACCCAU 362UAGAAGAAACGCUUUACCCA 363 UUAGAAGAAACGCUUUACCC 364 AAUCAUGCUUUCUGGGUAGA365 CUUAGGGCAGGAAAUCAUGC 366 ACUUAGGGCAGGAAAUCAUG 367GACUUAGGGCAGGAAAUCAU 368 AGGACUUAGGGCAGGAAAUC 369 CAGGACUUAGGGCAGGAAAU370 ACAGGACUUAGGGCAGGAAA 371 UCUCACAGGACUUAGGGCAG 372UUCUCACAGGACUUAGGGCA 373 AUCUUCUCACAGGACUUAGG 374 CAUCUUCUCACAGGACUUAG375 UAGUCCCUGACAUCUUCUCA 376 CUAGUCCCUGACAUCUUCUC 377CCUAGUCCCUGACAUCUUCU 378 CCCUAGUCCCUGACAUCUUC 379 UCCCUAGUCCCUGACAUCUU380 CUCCCUAGUCCCUGACAUCU 381 AUCUAUCUGCUUCCUCCUCC 382CCAUCUAUCUGCUUCCUCCU 383 ACCAUCUAUCUGCUUCCUCC 384 GACCAUCUAUCUGCUUCCUC385 GGACCAUCUAUCUGCUUCCU 386 UGGACCAUCUAUCUGCUUCC 387CUGGACCAUCUAUCUGCUUC 388 CUGCUGGACCAUCUAUCUGC 389 GCCUGCUGGACCAUCUAUCU390 UUCAAGCCUGCUGGACCAUC 391 UGCUUCAAGCCUGCUGGACC 392CCUCAACAGCCCUUACCCUG 393 UCCCUCUUGACCUUCCCUUA 394 CUCCCUCUUGACCUUCCCUU395 UCUCCCUCUUGACCUUCCCU 396 CAUCUCCCUCUUGACCUUCC 397CCAUCUCCCUCUUGACCUUC 398 CCCAUCUCCCUCUUGACCUU 399 GCCCAUCUCCCUCUUGACCU400 UUGCCCAUCUCCCUCUUGAC 401 CUUGCCCAUCUCCCUCUUGA 402CCCUAAGCAUCCUCCCUCAG 403 AACUUCUUAGGCUUAGUGCC 404 GGAACUUCUUAGGCUUAGUG405 GGGAACUUCUUAGGCUUAGU 406 AGGGAACUUCUUAGGCUUAG 407UGUCUCCCAGUGGGUCCUGU 408 AGUAUAAAUGCUUGUCUCCC 409 GACAGAGCGAGACUCGAUCU410 UGACAGAGCGAGACUCGAUC 411 GUGACAGAGCGAGACUCGAU 412GGUGACAGAGCGAGACUCGA 413 UGGUGACAGAGCGAGACUCG 414 CUGGUGACAGAGCGAGACUC415 CCUGGUGACAGAGCGAGACU 416 AGCCUGGUGACAGAGCGAGA 417UGCACUCCAGCCUGGUGACA 418 ACUGCACUCCAGCCUGGUGA 419 UCACUGCACUCCAGCCUGGU420 UGUCACUGCACUCCAGCCUG 421 GUGUCACUGCACUCCAGCCU 422AGACGGAGGUUGCAGUGAGC 423 GAGACGGAGGUUGCAGUGAG 424 GGAGACGGAGGUUGCAGUGA425 ACUUGAACCCAGGAGACGGA 426 CACUUGAACCCAGGAGACGG 427UCACUUGAACCCAGGAGACG 428 AUCACUUGAACCCAGGAGAC 429 AAUCACUUGAACCCAGGAGA430 GAAUCACUUGAACCCAGGAG 431 AGAAUCACUUGAACCCAGGA 432AAGAAUCACUUGAACCCAGG 433 GAAGAAUCACUUGAACCCAG 434 AGAAGAAUCACUUGAACCCA435 CAGAAGAAUCACUUGAACCC 436 GCAGAAGAAUCACUUGAACC 437GGCAGAAGAAUCACUUGAAC 438 AGGCAGAAGAAUCACUUGAA 439 GAGGCAGAAGAAUCACUUGA440 UGAGGCAGAAGAAUCACUUG 441 CUGAGGCAGAAGAAUCACUU 442GCUGAGGCAGAAGAAUCACU 443 GGCUGAGGCAGAAGAAUCAC 444 AGGCUGAGGCAGAAGAAUCA445 GAGGCUGAGGCAGAAGAAUC 446 GGAGGCUGAGGCAGAAGAAU 447GGGAGGCUGAGGCAGAAGAA 448 AGAUUGAGACCAUCCUGGCC 449 GAGAUUGAGACCAUCCUGGC450 AGAGAUUGAGACCAUCCUGG 451 AAGAGAUUGAGACCAUCCUG 452CAAGAGAUUGAGACCAUCCU 453 GGUGGCUCACGCCUAUAAUC 454 CGGUGGCUCACGCCUAUAAU455 GCGGUGGCUCACGCCUAUAA 456 CCCUAACCCUUCUUUAUGAC 457CACCCUAACCCUUCUUUAUG 458 AUCACCCUAACCCUUCUUUA 459 CAUCACCCUAACCCUUCUUU460 CCAUCACCCUAACCCUUCUU 461 GACCAUCACCCUAACCCUUC 462GGACCAUCACCCUAACCCUU 463 UGGACCAUCACCCUAACCCU 464 CUGGACCAUCACCCUAACCC465 UCUGGACCAUCACCCUAACC 466 CUCUGGACCAUCACCCUAAC 467GCUCUGGACCAUCACCCUAA 468 UGCUCUGGACCAUCACCCUA 469 GUUGCUCUGGACCAUCACCC470 UGUUGCUCUGGACCAUCACC 471 ACUGUUGCUCUGGACCAUCA 472AACUGUUGCUCUGGACCAUC 473 GAACUGUUGCUCUGGACCAU 474 GAAGAACUGUUGCUCUGGAC475 UUGAAGAACUGUUGCUCUGG 476 ACUUGAAGAACUGUUGCUCU 477CACUUGAAGAACUGUUGCUC 478 UACACUUGAAGAACUGUUGC 479 GAGUACACUUGAAGAACUGU480 AGAGUACACUUGAAGAACUG 481 CAGAGUACACUUGAAGAACU 482ACAGAGUACACUUGAAGAAC 483 CUACAGAGUACACUUGAAGA 484 CCUACAGAGUACACUUGAAG485 GCCUACAGAGUACACUUGAA 486 AGCCUACAGAGUACACUUGA 487AAGCCUACAGAGUACACUUG 488 CAGAAGCCUACAGAGUACAC 489 CCAGAAGCCUACAGAGUACA490 AAAAGGGACCUCCCAGAAGC 491 GAAAAGGGACCUCCCAGAAG 492UGAAAAGGGACCUCCCAGAA 493 CUUUGACUUUGUGGACACCC 494 GCUUUGACUUUGUGGACACC495 UAGCUUUGACUUUGUGGACA 496 AUAGCUUUGACUUUGUGGAC 497GUCACACGGCCUCUGGAAAA 498 UGUCACACGGCCUCUGGAAA 499 AUGUCACACGGCCUCUGGAA500

In some embodiments, the antisense nucleic acid molecules comprise orconsist of the nucleotide sequences shown in Table 2.

TABLE 2 SEQ ID Sequence NO: CUUAGUCACUUUUCCCAAGA 501UCUUAGUCACUUUUCCCAAG 502 CUCUUAGCAUCUUAGUCACU 503 GCUCUUAGCAUCUUAGUCAC504 UACGCUCUUAGCAUCUUAGU 505 AUACGCUCUUAGCAUCUUAG 506CUCAGCUAUAAAUACGCUCU 507 GCUCAGCUAUAAAUACGCUC 508 AGCUCAGCUAUAAAUACGCU509 ACCCUCACUGUCAGAUGCCC 510 CACCCUCACUGUCAGAUGCC 511CCCACCCUCACUGUCAGAUG 512 GGGAAGUGACAAGAAGUGGC 513 GUAUCAGUAGGCAGUCAGGG514 GGUAUCAGUAGGCAGUCAGG 515 GUUGGUAUCAGUAGGCAGUC 516UGUUGGUAUCAGUAGGCAGU 517 CCUGUUGGUAUCAGUAGGCA 518 ACCUGUUGGUAUCAGUAGGC519 CAGACGGCUUACCUGUUGGU 520 UCAGACGGCUUACCUGUUGG 521CUCAGACGGCUUACCUGUUG 522 CCUCAGACGGCUUACCUGUU 523 GCCUCAGACGGCUUACCUGU524 UGCCUCAGACGGCUUACCUG 525 GUGCCUCAGACGGCUUACCU 526UGGUGCCUCAGACGGCUUAC 527 GUGGUGCCUCAGACGGCUUA 528 AGCAAAGUGGAGGUAUCUAU529 GUCAGCAAAGUGGAGGUAUC 530 GGUCAGCAAAGUGGAGGUAU 531UUGGUCAGCAAAGUGGAGGU 532 AUUGGUCAGCAAAGUGGAGG 533 CAUUGGUCAGCAAAGUGGAG534 ACAUUGGUCAGCAAAGUGGA 535 AACAUUGGUCAGCAAAGUGG 536UGGAACAUUGGUCAGCAAAG 537 UCUGGAACAUUGGUCAGCAA 538 GGUCUGGAACAUUGGUCAGC539 GGGUCUGGAACAUUGGUCAG 540 CGGGUCUGGAACAUUGGUCA 541UCGGGUCUGGAACAUUGGUC 542 CUCGGGUCUGGAACAUUGGU 543 GGAAAUGACAGCCCUCUACC544 GGGAAAUGACAGCCCUCUAC 545 UGGGAAAUGACAGCCCUCUA 546GGUUGGGCUGGGAAAUGACA 547 UUGGUUGGGCUGGGAAAUGA 548 UGUUGGUUGGGCUGGGAAAU549 UCUGUUGGUUGGGCUGGGAA 550 AUUCUGUUGGUUGGGCUGGG 551CUCCCAGCAACCAUUCUGUU 552 GCUCCCAGCAACCAUUCUGU 553 AGCUCCCAGCAACCAUUCUG554 AGCUCUGUCCAGUGUUCUCC 555 CUGUCCACCCUGCAUUUCUC 556AUUAGACCCUCCUGUCCACC 557 GAUUAGACCCUCCUGUCCAC 558 CGAUUAGACCCUCCUGUCCA559 ACGAUUAGACCCUCCUGUCC 560 GACGAUUAGACCCUCCUGUC 561AGACGAUUAGACCCUCCUGU 562 GAGACGAUUAGACCCUCCUG 563 UGAGACGAUUAGACCCUCCU564 CUGAGACGAUUAGACCCUCC 565 ACUGAGACGAUUAGACCCUC 566CACUGAGACGAUUAGACCCU 567 GCACUGAGACGAUUAGACCC 568 CGCACUGAGACGAUUAGACC569 GCGCACUGAGACGAUUAGAC 570 GGCGCACUGAGACGAUUAGA 571ACCUCAGGGCACUCUUUGGU 572 AACCUCAGGGCACUCUUUGG 573 GAACCUCAGGGCACUCUUUG574 AGAACCUCAGGGCACUCUUU 575 UAGAACCUCAGGGCACUCUU 576CUAGAACCUCAGGGCACUCU 577 CCUAGAACCUCAGGGCACUC 578 UCCUAGAACCUCAGGGCACU579 GCUCUUCCUAGAACCUCAGG 580 CCAGGCUCUUCCUAGAACCU 581ACCAGGCUCUUCCUAGAACC 582 UACCAGGCUCUUCCUAGAAC 583 GUACCAGGCUCUUCCUAGAA584 UGUACCAGGCUCUUCCUAGA 585 AUGUACCAGGCUCUUCCUAG 586UGAUGUACCAGGCUCUUCCU 587 GGUGAUGUACCAGGCUCUUC 588 AUGGAGCUUGGUGAUGUACC589 UGGCAAUGGAGCUUGGUGAU 590 GUGGCAAUGGAGCUUGGUGA 591CGUGGCAAUGGAGCUUGGUG 592 ACGUGGCAAUGGAGCUUGGU 593 ACCUUUGGUUUUGGACCUCA594 UACCUUUGGUUUUGGACCUC 595 CUACCUUUGGUUUUGGACCU 596GCUACCUUUGGUUUUGGACC 597 ACUGCUACCUUUGGUUUUGG 598 CACUGCUACCUUUGGUUUUG599 UCACUGCUACCUUUGGUUUU 600 AUCACUGCUACCUUUGGUUU 601GAGAGACUGUCUUCAGGAUC 602 ACACUGCCAGAGAAGAGAGA 603 CACACUGCCAGAGAAGAGAG604 AGCUGGUUCCUUUGUUCUUU 605 GGGACAAGCUGGUUCCUUUG 606AGGGACAAGCUGGUUCCUUU 607 CAGGGACAAGCUGGUUCCUU 608 GACAGGGACAAGCUGGUUCC609 AGACAGGGACAAGCUGGUUC 610 AAGAGACAGGGACAAGCUGG 611CAAGAGACAGGGACAAGCUG 612 ACAAGAGACAGGGACAAGCU 613 AUGGAGUGAUGAGGAGUGCC614 CUGGCUUGUAGCUGGCUGGA 615 CCACCAGUGUCCACCAUGUG 616AGUACCACCAGUGUCCACCA 617 CAGUACCACCAGUGUCCACC 618 CCUCAGUACCACCAGUGUCC619 GACCUCAGUACCACCAGUGU 620 UGGACCUCAGUACCACCAGU 621GCUGGACCUCAGUACCACCA 622 AAGGCUGGACCUCAGUACCA 623 GAAGGCUGGACCUCAGUACC624 GGAAGGCUGGACCUCAGUAC 625 UUGGAAGGCUGGACCUCAGU 626AUUGGAAGGCUGGACCUCAG 627 AAUUGGAAGGCUGGACCUCA 628 CUAAUUGGAAGGCUGGACCU629 CCUAAUUGGAAGGCUGGACC 630 UCCUAAUUGGAAGGCUGGAC 631CUGUCAAGAGAGACUAUUAG 632 GCUGUCAAGAGAGACUAUUA 633 GGCUGUCAAGAGAGACUAUU634 GGGCUGUCAAGAGAGACUAU 635 CCCUCUGUUUAGAUGAUGGG 636CUCCACUUUGCUCAUCUCCC 637 UACUCCACUUUGCUCAUCUC 638 UUACUCCACUUUGCUCAUCU639 UUUACUCCACUUUGCUCAUC 640 CUUUACUCCACUUUGCUCAU 641UCUUUACUCCACUUUGCUCA 642 GUCUUUACUCCACUUUGCUC 643 GAAAUGUGUCUUUACUCCAC644 GUGUGAUUUGGAAAUGUGUC 645 GUGGGUGUGAUUUGGAAAUG 646AGUGGGUGUGAUUUGGAAAU 647 GAAGGUGGGCCUCAUGCUAG 648 CACCACACCCAGUCCUCACU649 AUGAGCCACCACACCCAGUC 650 CAUGAGCCACCACACCCAGU 651ACAUGAGCCACCACACCCAG 652 GACAUGAGCCACCACACCCA 653 AGACAUGAGCCACCACACCC654 UAGACAUGAGCCACCACACC 655 AUAGACAUGAGCCACCACAC 656GCUCAAGCGAUCCUCUCACC 657 GGCUCAAGCGAUCCUCUCAC 658 GGGCUCAAGCGAUCCUCUCA659 UGGGCUCAAGCGAUCCUCUC 660 CUGGGCUCAAGCGAUCCUCU 661UCUUUUGUAGAGACAGGGUC 662 UUCUUUUGUAGAGACAGGGU 663 AUUCUUUUGUAGAGACAGGG664 ACACCACACAGGCUAAUUUA 665 UGCCACCACACCAACCACAC 666GUGCCACCACACCAACCACA 667 GCUAAGUCUACAGGUGCGUG 668 UUGACCUCCUGGGUUAAGUG669 CUUGACCUCCUGGGUUAAGU 670 GCCUUGACCUCCUGGGUUAA 671UACAGGCAUGAGCCACCGCA 672 UUACAGGCAUGAGCCACCGC 673 AUUACAGGCAUGAGCCACCG674 GAUUACAGGCAUGAGCCACC 675 GGAUUACAGGCAUGAGCCAC 676GGGAUUACAGGCAUGAGCCA 677 UGGGAUUACAGGCAUGAGCC 678 CUGGGAUUACAGGCAUGAGC679 GCUGGGAUUACAGGCAUGAG 680 UGCUGGGAUUACAGGCAUGA 681GUGCUGGGAUUACAGGCAUG 682 AGUGCUGGGAUUACAGGCAU 683 AAGUGCUGGGAUUACAGGCA684 AAAGUGCUGGGAUUACAGGC 685 CAAAGUGCUGGGAUUACAGG 686CCAAAGUGCUGGGAUUACAG 687 GUUAGCCAGGAUGGUCUCCA 688 UGUUAGCCAGGAUGGUCUCC689 GUGUUAGCCAGGAUGGUCUC 690 UGUGUUAGCCAGGAUGGUCU 691CUGUGUUAGCCAGGAUGGUC 692 ACUGUGUUAGCCAGGAUGGU 693 CACUGUGUUAGCCAGGAUGG694 UCACUGUGUUAGCCAGGAUG 695 UUCACUGUGUUAGCCAGGAU 696UUUCACUGUGUUAGCCAGGA 697 GUUUCACUGUGUUAGCCAGG 698 GGUUUCACUGUGUUAGCCAG699 GGGUUUCACUGUGUUAGCCA 700 UUCUUCUGCCUCAGCCUCCC 701AUUCUUCUGCCUCAGCCUCC 702 CAUUCUUCUGCCUCAGCCUC 703 CCAUUCUUCUGCCUCAGCCU704 ACCAUUCUUCUGCCUCAGCC 705 CACCAUUCUUCUGCCUCAGC 706ACACCAUUCUUCUGCCUCAG 707 CUCACUGCAAGCUCCACCUC 708 GCUCACUGCAAGCUCCACCU709 UCGGCUCACUGCAAGCUCCA 710 UCUCGGCUCACUGCAAGCUC 711AUCUCGGCUCACUGCAAGCU 712 AAUCUCGGCUCACUGCAAGC 713 CAAUCUCGGCUCACUGCAAG714 ACAAUCUCGGCUCACUGCAA 715 CACAAUCUCGGCUCACUGCA 716GCACAAUCUCGGCUCACUGC 717 GGCACAAUCUCGGCUCACUG 718 UGGCACAAUCUCGGCUCACU719 GUGGCACAAUCUCGGCUCAC 720 AGUGGCACAAUCUCGGCUCA 721CAGUGGCACAAUCUCGGCUC 722 GCAGUGGCACAAUCUCGGCU 723 UGCAGUGGCACAAUCUCGGC724 AGGCUGAGUCUCGCUCUGUC 725 CCACAUUUUCUCACUGUCUU 726CUCCUGACCACAUUUUCUCA 727 CCUCCUGACCACAUUUUCUC 728 CCCUCCUGACCACAUUUUCU729 GCCCUCCUGACCACAUUUUC 730 UCUUGGUUCCCAGUCUCAGC 731GCAGUCUUGGUUCCCAGUCU 732 CAGCAGUCUUGGUUCCCAGU 733 UACAGCAGUCUUGGUUCCCA734 AUACAGCAGUCUUGGUUCCC 735 CAAAUACAGCAGUCUUGGUU 736GCAAAUACAGCAGUCUUGGU 737 GGCAAAUACAGCAGUCUUGG 738 AAGGCAAAUACAGCAGUCUU739 CAAGGCAAAUACAGCAGUCU 740 GCAAGGCAAAUACAGCAGUC 741AGCAAGGCAAAUACAGCAGU 742 AAAGCAAGGCAAAUACAGCA 743 CAAAGCAAGGCAAAUACAGC744 UUGACAACAAAGCAAGGCAA 745 CUCUAAGAGCUUUUGACAAC 746UUGCCUCAGCCUCCUAAAGU 747 CUUGCCUCAGCCUCCUAAAG 748 ACUUGCCUCAGCCUCCUAAA749 CACUUGCCUCAGCCUCCUAA 750 UGAUGUGGAGGAGGGCCAGA 837AUGAUGUGGAGGAGGGCCAG 838 CAUGAUGUGGAGGAGGGCCA 839 GGAGCAUGAUGUGGAGGAGG840 UGGAGCAUGAUGUGGAGGAG 841 GUGGAGCAUGAUGUGGAGGA 842UGUGGAGCAUGAUGUGGAGG 843 AUGUGGAGCAUGAUGUGGAG 844 GAUGUGGAGCAUGAUGUGGA845 UGAUGUGGAGCAUGAUGUGG 846 AUGAUGUGGAGCAUGAUGUG 847UGGAGCAUGAUGUGGAGCAU 848 GCCUGGAGCAUGAUGUGGAG 849 GGCCUGGAGCAUGAUGUGGA850 UGGCCUGGAGCAUGAUGUGG 851 UUGGCCUGGAGCAUGAUGUG 852GUUGGCCUGGAGCAUGAUGU 853 AGUUGGCCUGGAGCAUGAUG 854 CAGUUGGCCUGGAGCAUGAU855 GCCACGAGGCACAGAAGUCA 856 GAGAAUGGAGCCCUCUUGCU 857GGUAGGAGAAUGGAGCCCUC 858 GGGUAGGAGAAUGGAGCCCU 859 ACAGGGAUGAGGGUUUGGGC860 UAGGACAGGGAUGAGGGUUU 861 CUAGGACAGGGAUGAGGGUU 862UUCCAGUGGGUAUUCCUCUG 863 GUUCCAGUGGGUAUUCCUCU 864 AGUUCCAGUGGGUAUUCCUC865 GCAGUUUCCAUGAGGCAGCU 866 UGCAGCAGUUUCCAUGAGGC 867CUAGCUUCACCACUGCUGCA 868 CUUUCUAGCUUCACCACUGC 869 UAGUCUUUCUAGCUUCACCA870 CUCAUACCUCUAGUCUUUCU 871 CCUCAUACCUCUAGUCUUUC 872CCCUCAUACCUCUAGUCUUU 873 UCCCUCAUACCUCUAGUCUU 874 UUCCCUCAUACCUCUAGUCU875 UUUCCCUCAUACCUCUAGUC 876 UUUUCCCUCAUACCUCUAGU 877AUUUUCCCUCAUACCUCUAG 878 GCAAUUUUCCCUCAUACCUC 879 ACGCCUUAUGAGCCAGGUGG880 AACGCCUUAUGAGCCAGGUG 881 GAACGCCUUAUGAGCCAGGU 882GGGAACGCCUUAUGAGCCAG 883 AGGGAACGCCUUAUGAGCCA 884 GAGGGAACGCCUUAUGAGCC885 GGAGGGAACGCCUUAUGAGC 886 GGGAGGGAACGCCUUAUGAG 887GAUGAUUUCACAUGCUCAGU 888 AGGAUGAUUUCACAUGCUCA 889 GAGGAUGAUUUCACAUGCUC890 AGAGGAUGAUUUCACAUGCU 891 CAUGAUGCAAGAAAGAGGAU 892GCAUGAUGCAAGAAAGAGGA 893 CACGCAUGAUGCAAGAAAGA 894 ACACGCAUGAUGCAAGAAAG895 GACACGCAUGAUGCAAGAAA 896 GGACACGCAUGAUGCAAGAA 897UGGACACGCAUGAUGCAAGA 898 GUGGACACGCAUGAUGCAAG 899 UGUGGACACGCAUGAUGCAA900 AUGUGGACACGCAUGAUGCA 901 CAAUGUGGACACGCAUGAUG 902GCAAUGUGGACACGCAUGAU 903 GUGCAAUGUGGACACGCAUG 904 GGUGCAAUGUGGACACGCAU905 GGGUGCAAUGUGGACACGCA 906 UGACUGGGCCUGAAGUAGGG 907CAUGGUGACUGGGCCUGAAG 908 CUCAGGUUUCACCAUCUGGC 909 CAGCUCAGGUUUCACCAUCU910 UCAGCUCAGGUUUCACCAUC 911 AUCAGCUCAGGUUUCACCAU 912CAUCAGCUCAGGUUUCACCA 913 UCUGAGUCCCAGGAUUGGCC 914 CCUCUGAGUCCCAGGAUUGG915 CCCUCUGAGUCCCAGGAUUG 916 ACCCUCUGAGUCCCAGGAUU 917UACCCUCUGAGUCCCAGGAU 918 CUACCCUCUGAGUCCCAGGA 919 AGCCGACCUACCCUCUGAGU920 AACCUAGUGGUCAGCCAGCC 921 AAACCUAGUGGUCAGCCAGC 922CCAAACCUAGUGGUCAGCCA 923 UCCAAACCUAGUGGUCAGCC 924 UUCCAAACCUAGUGGUCAGC925 UCUUCCAAACCUAGUGGUCA 926 GUCUUCCAAACCUAGUGGUC 927GGUCUUCCAAACCUAGUGGU 928 GGGUCUUCCAAACCUAGUGG 929 UGGGUCUUCCAAACCUAGUG930 CUGGGUCUUCCAAACCUAGU 931 CCUGGGUCUUCCAAACCUAG 932GCUGCCUGGGUCUUCCAAAC 933 GGGCCUCUUUAGAGCCAGCU 934 AUGUCUGGCUACUGACCUGG935 UCAUGUCUGGCUACUGACCU 936 CUCAUGUCUGGCUACUGACC 937GCUCAUGUCUGGCUACUGAC 938 AGCUCAUGUCUGGCUACUGA 939 CAGCUCAUGUCUGGCUACUG940 ACAGCUCAUGUCUGGCUACU 941 UGACCCUCACAGCUCAUGUC 942UUGACCCUCACAGCUCAUGU 943 UGCUUGACCCUCACAGCUCA 944 GUGCUUGACCCUCACAGCUC945 UAGCUGUGCUUGACCCUCAC 946 AUAGCUGUGCUUGACCCUCA 947GAUAGCUGUGCUUGACCCUC 948 GGAUAGCUGUGCUUGACCCU 949 UGGAUAGCUGUGCUUGACCC950 AUGGAUAGCUGUGCUUGACC 951 GAUGGAUAGCUGUGCUUGAC 952UGAUGGAUAGCUGUGCUUGA 953 AUCUGAUGGAUAGCUGUGCU 954 CAUCUGAUGGAUAGCUGUGC955 AUCAUCUGAUGGAUAGCUGU 956 GAUCAUCUGAUGGAUAGCUG 957AGAUCAUCUGAUGGAUAGCU 958 UAGAUCAUCUGAUGGAUAGC 959 GUAGAUCAUCUGAUGGAUAG960 GAAAGUAGAUCAUCUGAUGG 961 GCUGAAAGUAGAUCAUCUGA 962AGGCUGAAAGUAGAUCAUCU 963 AAGGCUGAAAGUAGAUCAUC 964 GAAGGCUGAAAGUAGAUCAU965 GGAAGGCUGAAAGUAGAUCA 966 AGGAAGGCUGAAAGUAGAUC 967GUCUGGGACUCAGGAAGGCU 968 UAUUGUCUGGGACUCAGGAA 969 CUAUUGUCUGGGACUCAGGA970 UCUAUUGUCUGGGACUCAGG 971 CUUCUAUUGUCUGGGACUCA 972UCUUCUAUUGUCUGGGACUC 973 CACCUGUCUUCUAUUGUCUG 974 CCACCUGUCUUCUAUUGUCU975 GCCACCUGUCUUCUAUUGUC 976 AGCCACCUGUCUUCUAUUGU 977AUGAGGGCACAGUGACAGCA 978 CAAUGAGGGCACAGUGACAG 979 CCAAUGAGGGCACAGUGACA980 CGUCUGUUGAGUCUGAUUGC 981 CCGUCUGUUGAGUCUGAUUG 982UCCGUCUGUUGAGUCUGAUU 983 CUCCGUCUGUUGAGUCUGAU 984 GCUCCGUCUGUUGAGUCUGA985 UGCUCCGUCUGUUGAGUCUG 986 UUGCUCCGUCUGUUGAGUCU 987AGUUGCUCCGUCUGUUGAGU 988 GCAGUUGCUCCGUCUGUUGA 989 GGCAGUUGCUCCGUCUGUUG990 GAUGGCAGUUGCUCCGUCUG 991 GGAUGGCAGUUGCUCCGUCU 992AGCCUCGGAUGGCAGUUGCU 993 AGGAGCCUCGGAUGGCAGUU 994 UUCAGGAGCCUCGGAUGGCA995 UGGUUCAGGAGCCUCGGAUG 996 CUGGUUCAGGAGCCUCGGAU 997CUGGUGAAUGGCCCUGGUUC 998 CCUGGUGAAUGGCCCUGGUU 999 UCCUGGUGAAUGGCCCUGGU1000 UGGACAUCAGGGAGCCGCAU 1001 AGGAUUUGCUGCUUGGCUAG 1002CAGGAUUUGCUGCUUGGCUA 1003 UCCAGGAUUUGCUGCUUGGC 1004 ACCCAUCCAGGAUUUGCUGC1005 AACCCAUCCAGGAUUUGCUG 1006 CAACCCAUCCAGGAUUUGCU 1007UGCAACCCAUCCAGGAUUUG 1008 GUGCAACCCAUCCAGGAUUU 1009 GGUGCAACCCAUCCAGGAUU1010 AGGUGCAACCCAUCCAGGAU 1011 CAGGUGCAACCCAUCCAGGA 1012UCAGGUGCAACCCAUCCAGG 1013 GUCAGGUGCAACCCAUCCAG 1014 GGUCAGGUGCAACCCAUCCA1015 UGGUCAGGUGCAACCCAUCC 1016 CUGGUCAGGUGCAACCCAUC 1017ACUGGUCAGGUGCAACCCAU 1018 GACUGGUCAGGUGCAACCCA 1019 ACGACUGGUCAGGUGCAACC1020 GACGACUGGUCAGGUGCAAC 1021 GGACGACUGGUCAGGUGCAA 1022UCUGGGACGACUGGUCAGGU 1023 UUCUGGGACGACUGGUCAGG 1024 AUUCUGGGACGACUGGUCAG1025 UAUUCUGGGACGACUGGUCA 1026 UUAUUCUGGGACGACUGGUC 1027GUUAUUCUGGGACGACUGGU 1028 AGUUAUUCUGGGACGACUGG 1029 GAGUUAUUCUGGGACGACUG1030 UGAGUUAUUCUGGGACGACU 1031 AUGAGUUAUUCUGGGACGAC 1032GAUGAGUUAUUCUGGGACGA 1033 GGAUGAGUUAUUCUGGGACG 1034 UGGAGGAUGAGUUAUUCUGG1035 GUGGAGGAUGAGUUAUUCUG 1036 GGUGGAGGAUGAGUUAUUCU 1037GGGUGGAGGAUGAGUUAUUC 1038 AAAGCUGAUGACCUCCUCCC 1039 CAAAGCUGAUGACCUCCUCC1040 AGCAAAGCUGAUGACCUCCU 1041 UAGCAAAGCUGAUGACCUCC 1042GUAGCAAAGCUGAUGACCUC 1043 AGUAGCAAAGCUGAUGACCU 1044 ACAGUAGCAAAGCUGAUGAC1045 UGACAGUAGCAAAGCUGAUG 1046 GUGACAGUAGCAAAGCUGAU 1047ACCUGUGACAGUAGCAAAGC 1048 CACCUGUGACAGUAGCAAAG 1049 CCACCUGUGACAGUAGCAAA1050 CCCACCUGUGACAGUAGCAA 1051 ACCCACCUGUGACAGUAGCA 1052CACCCACCUGUGACAGUAGC 1053 GUUGCUCUCUCCCUCACCCA 1054 CCUGUUGCUCUCUCCCUCAC1055 GCCUGUUGCUCUCUCCCUCA 1056 UGCCUGUUGCUCUCUCCCUC 1057CCCUGUCUGCUCUUUGCCUG 1058 UUUCCCUGUCUGCUCUUUGC 1059 UCCUCUGCAACCAGUCCCUG1060 GUCCUCUGCAACCAGUCCCU 1061 GUGUCCUCUGCAACCAGUCC 1062UGUGUCCUCUGCAACCAGUC 1063 UUGUGUCCUCUGCAACCAGU 1064 ACUGCUUUGUGUCCUCUGCA1065 GACUGCUUUGUGUCCUCUGC 1066 GAGACUGCUUUGUGUCCUCU 1067AGAGACUGCUUUGUGUCCUC 1068 UAGAGACUGCUUUGUGUCCU 1069 UCCCUCGAACCUACCUCUAG1070 CUCCCUCGAACCUACCUCUA 1071 UCUCCCUCGAACCUACCUCU 1072CUCUCCCUCGAACCUACCUC 1073 ACUGCUCUCCCUCGAACCUA 1074 AGAUGAAGCUCUCCUCUGAG1075 AUGUGAGUAGAGAUGAAGCU 1076 UGCCCGAAAGACAGAAAAGG 1077CUGCCCGAAAGACAGAAAAG 1078 AGUGGAGUCUGCCCGAAAGA 1079 AAGUGGAGUCUGCCCGAAAG1080 GAAGUGGAGUCUGCCCGAAA 1081 AGGCUGAAGUGGAGUCUGCC 1082UAGGCUGAAGUGGAGUCUGC 1083 GUAGGCUGAAGUGGAGUCUG 1084 GCUGUAGGCUGAAGUGGAGU1085 AGCUGUAGGCUGAAGUGGAG 1086 GAGCUGUAGGCUGAAGUGGA 1087GGGAGCUGUAGGCUGAAGUG 1088 AGGGAGCUGUAGGCUGAAGU 1089 AAGUGAGCAGGGAGCUGUAG1090 UGGACAGGUGAAAAGUGAGC 1091 GUGGACAGGUGAAAAGUGAG 1092AGUGGACAGGUGAAAAGUGA 1093 GAGUGGACAGGUGAAAAGUG 1094 GGAGUGGACAGGUGAAAAGU1095 AGGAGUGGACAGGUGAAAAG 1096 GAGGAGUGGACAGGUGAAAA 1097CGAGGAGUGGACAGGUGAAA 1098 CCGAGGAGUGGACAGGUGAA 1099 ACCGAGGAGUGGACAGGUGA1100 CAUGGUACAGGUGGUGGGAC 1101 GCAUGGUACAGGUGGUGGGA 1102CAAAGAGUGCCAGGAAGGGU 1103 GCAAAGAGUGCCAGGAAGGG 1104 AAGCAAAGAGUGCCAGGAAG1105 UCAAGCAAAGAGUGCCAGGA 1106 CUCAAGCAAAGAGUGCCAGG 1107CCUCAAGCAAAGAGUGCCAG 1108 AUCCUCAAGCAAAGAGUGCC 1109 GAUCCUCAAGCAAAGAGUGC1110 GAAGAUCCUCAAGCAAAGAG 1111 GGAAGAUCCUCAAGCAAAGA 1112CGGAAGAUCCUCAAGCAAAG 1113 AUCGGAAGAUCCUCAAGCAA 1114 CAUCGGAAGAUCCUCAAGCA1115 CCAUCGGAAGAUCCUCAAGC 1116 CCCAUCGGAAGAUCCUCAAG 1117AUGUGGUGCUCAGCCAGGAG 1118 UUGGUGAUGUGGUGCUCAGC 1119 GGUUGGUGAUGUGGUGCUCA1120 AGGUUGGUGAUGUGGUGCUC 1121 CAGGUUGGUGAUGUGGUGCU 1122AGCCCAGGUUGGUGAUGUGG 1123 CAGCCCAGGUUGGUGAUGUG 1124 UGCCAGCCCAGGUUGGUGAU1125 AUGCCAGCCCAGGUUGGUGA 1126 GUAUGCCAGCCCAGGUUGGU 1127AGGUAUGCCAGCCCAGGUUG 1128 AAGGUAUGCCAGCCCAGGUU 1129 UAAGGUAUGCCAGCCCAGGU1130 UUAAGGUAUGCCAGCCCAGG 1131 GUUAAGGUAUGCCAGCCCAG 1132AGUUAAGGUAUGCCAGCCCA 1133 GAGUUAAGGUAUGCCAGCCC 1134 AGAGUUAAGGUAUGCCAGCC1135 CAGAGUUAAGGUAUGCCAGC 1136 GCAGAGUUAAGGUAUGCCAG 1137AGGGCAGAGUUAAGGUAUGC 1138 AGAGGGCAGAGUUAAGGUAU 1139 UAGAGGGCAGAGUUAAGGUA1140 CUAGAGGGCAGAGUUAAGGU 1141 CACUAGAGGGCAGAGUUAAG 1142GCCACUAGAGGGCAGAGUUA 1143 GGACACCAGACUUCUCACCC 1144 AGGACACCAGACUUCUCACC1145 CAGGACACCAGACUUCUCAC 1146 UUUCAGGACACCAGACUUCU 1147GUUUCAGGACACCAGACUUC 1148 UAGUUGCAGUUUCAGGACAC 1149 CUAGUUGCAGUUUCAGGACA1150 UCUAGUUGCAGUUUCAGGAC 1151 GUCUAGUUGCAGUUUCAGGA 1152AGUCUAGUUGCAGUUUCAGG 1153 CAGUCUAGUUGCAGUUUCAG 1154 AACUGUGCUGUUGCCUUCUA1155 UAACUGUGCUGUUGCCUUCU 1156 GUAACUGUGCUGUUGCCUUC 1157CCAGUAACUGUGCUGUUGCC 1158 GUCCAGUAACUGUGCUGUUG 1159 UGUCCAGUAACUGUGCUGUU1160 UUGUCCAGUAACUGUGCUGU 1161 GGUUGUCCAGUAACUGUGCU 1162CGGUUGUCCAGUAACUGUGC 1163 UCGGUUGUCCAGUAACUGUG 1164 CUCGGUUGUCCAGUAACUGU1165 CCUCGGUUGUCCAGUAACUG 1166 GCCUCGGUUGUCCAGUAACU 1167CGCCUCGGUUGUCCAGUAAC 1168 CCGCCUCGGUUGUCCAGUAA 1169 UGCUGGUGUCCUGCUGUGUC1170 CUGCUGGUGUCCUGCUGUGU 1171 UCUAGGAAGGGCUGCUGGUG 1172UUAAGCUCUAGGAAGGGCUG 1173 CUCAUUGGCUCGGAUCUUAA 1174 GCUCAUUGGCUCGGAUCUUA1175 GGCUCAUUGGCUCGGAUCUU 1176 AGGCUCAUUGGCUCGGAUCU 1177CAGGCUCAUUGGCUCGGAUC 1178 UCCAGGCUCAUUGGCUCGGA 1179 UCUCGCCUGCAACAUAAGGG1180 CAGAAUGGAAAGAGGCAGCA 1181 GCAGAAUGGAAAGAGGCAGC 1182AAGACGGCAGAAUGGAAAGA 1183 GAAGACGGCAGAAUGGAAAG 1184 UGAAGACGGCAGAAUGGAAA1185 CUGAAGACGGCAGAAUGGAA 1186 GCUGAAGACGGCAGAAUGGA 1187GGCUGAAGACGGCAGAAUGG 1188 AGGCUGAAGACGGCAGAAUG 1189 GGAGGCUGAAGACGGCAGAA1190 AGGAGGCUGAAGACGGCAGA 1191 UGUUGGCUUUGAGGAGGCUG 1192CAAGGAUUGUUGGCUUUGAG 1193 UGGCAGGCCAAGGAUUGUUG 1194 CUGGCAGGCCAAGGAUUGUU1195 ACUGGCAGGCCAAGGAUUGU 1196 AGGAGGUACUGGCAGGCCAA 1197AACAGGAGGUACUGGCAGGC 1198 CAACAGGAGGUACUGGCAGG 1199 ACACAACAGGAGGUACUGGC1200 AGGGACACAACAGGAGGUAC 1201 UCGGGCAGUAGGGACACAAC 1202UUCGGGCAGUAGGGACACAA 1203 CUUCGGGCAGUAGGGACACA 1204 AUGAUCCAGGUAGAGGAGAG1205 UAUGAUCCAGGUAGAGGAGA 1206 UUAUGAUCCAGGUAGAGGAG 1207AUUAUGAUCCAGGUAGAGGA 1208 CAUUAUGAUCCAGGUAGAGG 1209 CCAUUAUGAUCCAGGUAGAG1210 UGCCAUUAUGAUCCAGGUAG 1211 UUGCCAUUAUGAUCCAGGUA 1212AUUGCCAUUAUGAUCCAGGU 1213 CAUUGCCAUUAUGAUCCAGG 1214 ACAUUGCCAUUAUGAUCCAG1215 CCACAUUGCCAUUAUGAUCC 1216 GACCACAUUGCCAUUAUGAU 1217UGACCACAUUGCCAUUAUGA 1218 UUGACCACAUUGCCAUUAUG 1219 UCUUGACCACAUUGCCAUUA1220 GUCUUGACCACAUUGCCAUU 1221 CGUCUUGACCACAUUGCCAU 1222CCGUCUUGACCACAUUGCCA 1223 UCCGUCUUGACCACAUUGCC 1224 AUCCGUCUUGACCACAUUGC1225 CAUCCGUCUUGACCACAUUG 1226 ACAUCCGUCUUGACCACAUU 1227CACAUCCGUCUUGACCACAU 1228 GCACAUCCGUCUUGACCACA 1229 GGCACAUCCGUCUUGACCAC1230 UGGCACAUCCGUCUUGACCA 1231 CUGGCACAUCCGUCUUGACC 1232UCUGGCACAUCCGUCUUGAC 1233 AUCUGGCACAUCCGUCUUGA 1234 UAUCUGGCACAUCCGUCUUG1235 AUAUCUGGCACAUCCGUCUU 1236 CAUAUCUGGCACAUCCGUCU 1237CCAUAUCUGGCACAUCCGUC 1238 CACCAUAUCUGGCACAUCCG 1239 CUCCACCACCAUAUCUGGCA1240 UGGUCUCUUCACUCCAAAGC 1241 CUUCAUCUUGGUCUCUUCAC 1242ACUUCAUCUUGGUCUCUUCA 1243 AACUUCAUCUUGGUCUCUUC 1244 GGAAACUUCAUCUUGGUCUC1245 CCUCCAGUCACAGAUGCCCU 1246 GAUGCCUCCAGUCACAGAUG 1247UGAUGCCUCCAGUCACAGAU 1248 CAGGUGGUUGUUGGGUUGGG 1249 CCAGGUGGUUGUUGGGUUGG1250 GCCAGGUGGUUGUUGGGUUG 1251 UGCCAGGUGGUUGUUGGGUU 1252CAUAUUGCCAGGUGGUUGUU 1253 UCAUAUUGCCAGGUGGUUGU 1254 GUCAUAUUGCCAGGUGGUUG1255 AGUCAUAUUGCCAGGUGGUU 1256 GAGUCAUAUUGCCAGGUGGU 1257AGUGAGUCAUAUUGCCAGGU 1258 AAGUGAGUCAUAUUGCCAGG 1259 CAAGUGAGUCAUAUUGCCAG1260 GUCAAGUGAGUCAUAUUGCC 1261 GGUCAAGUGAGUCAUAUUGC 1262GGGUCAAGUGAGUCAUAUUG 1263 CCCAUUUGGGUCCCAUAGGG 1264 GCCCAUUUGGGUCCCAUAGG1265 UGCCCAUUUGGGUCCCAUAG 1266 GUGCCCAUUUGGGUCCCAUA 1267AGUGCCCAUUUGGGUCCCAU 1268 AAGUGCCCAUUUGGGUCCCA 1269 AAAGUGCCCAUUUGGGUCCC1270 GAAAGUGCCCAUUUGGGUCC 1271 AGAAAGUGCCCAUUUGGGUC 1272CAAGAAAGUGCCCAUUUGGG 1273 ACAAGAAAGUGCCCAUUUGG 1274 GACAAGAAAGUGCCCAUUUG1275 GAGUCUCAGACAAGAAAGUG 1276 CCAGAGUCUCAGACAAGAAA 1277GCCAGAGUCUCAGACAAGAA 1278 AGCCAGAGUCUCAGACAAGA 1279 UAAGCCAGAGUCUCAGACAA1280 AUAAGCCAGAGUCUCAGACA 1281 AGCCAACCUGGAAUAAGCCA 1282UCAGCCAACCUGGAAUAAGC 1283 CAUCAGCCAACCUGGAAUAA 1284 CACAUCAGCCAACCUGGAAU1285 ACACAUCAGCCAACCUGGAA 1286 AACACAUCAGCCAACCUGGA 1287CAACACAUCAGCCAACCUGG 1288 CUCCCAACACAUCAGCCAAC 1289 CGCUUUACCCAUCUCCCAAC1290 AACGCUUUACCCAUCUCCCA 1291 AAACGCUUUACCCAUCUCCC 1292AGAAACGCUUUACCCAUCUC 1293 AAGAAACGCUUUACCCAUCU 1294 GAAGAAACGCUUUACCCAUC1295 AGAAGAAACGCUUUACCCAU 1296 UAGAAGAAACGCUUUACCCA 1297UUAGAAGAAACGCUUUACCC 1298 AAUCAUGCUUUCUGGGUAGA 1299 CUUAGGGCAGGAAAUCAUGC1300 ACUUAGGGCAGGAAAUCAUG 1301 GACUUAGGGCAGGAAAUCAU 1302AGGACUUAGGGCAGGAAAUC 1303 CAGGACUUAGGGCAGGAAAU 1304 ACAGGACUUAGGGCAGGAAA1305 UCUCACAGGACUUAGGGCAG 1306 UUCUCACAGGACUUAGGGCA 1307AUCUUCUCACAGGACUUAGG 1308 CAUCUUCUCACAGGACUUAG 1309 UAGUCCCUGACAUCUUCUCA1310 CUAGUCCCUGACAUCUUCUC 1311 CCUAGUCCCUGACAUCUUCU 1312CCCUAGUCCCUGACAUCUUC 1313 UCCCUAGUCCCUGACAUCUU 1314 CUCCCUAGUCCCUGACAUCU1315 AUCUAUCUGCUUCCUCCUCC 1316 CCAUCUAUCUGCUUCCUCCU 1317ACCAUCUAUCUGCUUCCUCC 1318 GACCAUCUAUCUGCUUCCUC 1319 GGACCAUCUAUCUGCUUCCU1320 UGGACCAUCUAUCUGCUUCC 1321 CUGGACCAUCUAUCUGCUUC 1322CUGCUGGACCAUCUAUCUGC 1323 GCCUGCUGGACCAUCUAUCU 1324 UUCAAGCCUGCUGGACCAUC1325 UGCUUCAAGCCUGCUGGACC 1326 CCUCAACAGCCCUUACCCUG 1327UCCCUCUUGACCUUCCCUUA 1328 CUCCCUCUUGACCUUCCCUU 1329 UCUCCCUCUUGACCUUCCCU1330 CAUCUCCCUCUUGACCUUCC 1331 CCAUCUCCCUCUUGACCUUC 1332CCCAUCUCCCUCUUGACCUU 1333 GCCCAUCUCCCUCUUGACCU 1334 UUGCCCAUCUCCCUCUUGAC1335 CUUGCCCAUCUCCCUCUUGA 1336 CCCUAAGCAUCCUCCCUCAG 1337AACUUCUUAGGCUUAGUGCC 1338 GGAACUUCUUAGGCUUAGUG 1339 GGGAACUUCUUAGGCUUAGU1340 AGGGAACUUCUUAGGCUUAG 1341 UGUCUCCCAGUGGGUCCUGU 1342AGUAUAAAUGCUUGUCUCCC 1343 GACAGAGCGAGACUCGAUCU 1344 UGACAGAGCGAGACUCGAUC1345 GUGACAGAGCGAGACUCGAU 1346 GGUGACAGAGCGAGACUCGA 1347UGGUGACAGAGCGAGACUCG 1348 CUGGUGACAGAGCGAGACUC 1349 CCUGGUGACAGAGCGAGACU1350 AGCCUGGUGACAGAGCGAGA 1351 UGCACUCCAGCCUGGUGACA 1352ACUGCACUCCAGCCUGGUGA 1353 UCACUGCACUCCAGCCUGGU 1354 UGUCACUGCACUCCAGCCUG1355 GUGUCACUGCACUCCAGCCU 1356 AGACGGAGGUUGCAGUGAGC 1357GAGACGGAGGUUGCAGUGAG 1358 GGAGACGGAGGUUGCAGUGA 1359 ACUUGAACCCAGGAGACGGA1360 CACUUGAACCCAGGAGACGG 1361 UCACUUGAACCCAGGAGACG 1362AUCACUUGAACCCAGGAGAC 1363 AAUCACUUGAACCCAGGAGA 1364 GAAUCACUUGAACCCAGGAG1365 AGAAUCACUUGAACCCAGGA 1366 AAGAAUCACUUGAACCCAGG 1367GAAGAAUCACUUGAACCCAG 1368 AGAAGAAUCACUUGAACCCA 1369 CAGAAGAAUCACUUGAACCC1370 GCAGAAGAAUCACUUGAACC 1371 GGCAGAAGAAUCACUUGAAC 1372AGGCAGAAGAAUCACUUGAA 1373 GAGGCAGAAGAAUCACUUGA 1374 UGAGGCAGAAGAAUCACUUG1375 CUGAGGCAGAAGAAUCACUU 1376 GCUGAGGCAGAAGAAUCACU 1377GGCUGAGGCAGAAGAAUCAC 1378 AGGCUGAGGCAGAAGAAUCA 1379 GAGGCUGAGGCAGAAGAAUC1380 GGAGGCUGAGGCAGAAGAAU 1381 GGGAGGCUGAGGCAGAAGAA 1382AGAUUGAGACCAUCCUGGCC 1383 GAGAUUGAGACCAUCCUGGC 1384 AGAGAUUGAGACCAUCCUGG1385 AAGAGAUUGAGACCAUCCUG 1386 CAAGAGAUUGAGACCAUCCU 1387GGUGGCUCACGCCUAUAAUC 1388 CGGUGGCUCACGCCUAUAAU 1389 GCGGUGGCUCACGCCUAUAA1390 CCCUAACCCUUCUUUAUGAC 1391 CACCCUAACCCUUCUUUAUG 1392AUCACCCUAACCCUUCUUUA 1393 CAUCACCCUAACCCUUCUUU 1394 CCAUCACCCUAACCCUUCUU1395 GACCAUCACCCUAACCCUUC 1396 GGACCAUCACCCUAACCCUU 1397UGGACCAUCACCCUAACCCU 1398 CUGGACCAUCACCCUAACCC 1399 UCUGGACCAUCACCCUAACC1400 CUCUGGACCAUCACCCUAAC 1401 GCUCUGGACCAUCACCCUAA 1402UGCUCUGGACCAUCACCCUA 1403 GUUGCUCUGGACCAUCACCC 1404 UGUUGCUCUGGACCAUCACC1405 ACUGUUGCUCUGGACCAUCA 1406 AACUGUUGCUCUGGACCAUC 1407GAACUGUUGCUCUGGACCAU 1408 GAAGAACUGUUGCUCUGGAC 1409 UUGAAGAACUGUUGCUCUGG1410 ACUUGAAGAACUGUUGCUCU 1411 CACUUGAAGAACUGUUGCUC 1412UACACUUGAAGAACUGUUGC 1413 GAGUACACUUGAAGAACUGU 1414 AGAGUACACUUGAAGAACUG1415 CAGAGUACACUUGAAGAACU 1416 ACAGAGUACACUUGAAGAAC 1417CUACAGAGUACACUUGAAGA 1418 CCUACAGAGUACACUUGAAG 1419 GCCUACAGAGUACACUUGAA1420 AGCCUACAGAGUACACUUGA 1421 AAGCCUACAGAGUACACUUG 1422CAGAAGCCUACAGAGUACAC 1423 CCAGAAGCCUACAGAGUACA 1424 AAAAGGGACCUCCCAGAAGC1425 GAAAAGGGACCUCCCAGAAG 1426 UGAAAAGGGACCUCCCAGAA 1427CUUUGACUUUGUGGACACCC 1428 GCUUUGACUUUGUGGACACC 1429 UAGCUUUGACUUUGUGGACA1430 AUAGCUUUGACUUUGUGGAC 1431 GUCACACGGCCUCUGGAAAA 1432UGUCACACGGCCUCUGGAAA 1433 AUGUCACACGGCCUCUGGAA 1434 AAGACCAUACAAGCACACAU1435 ACAAGACCAUACAAGCACAC 1436 CACAAGACCAUACAAGCACA 1437AACACAAGACCAUACAAGCA 1438 UAACACAAGACCAUACAAGC 1439 ACUGUAACACAAGACCAUAC1440 AGACUGUAACACAAGACCAU 1441 AAGACUGUAACACAAGACCA 1442GCCGAGAUUGUGCCACUGCA 1443 AGCCGAGAUUGUGCCACUGC 1444 GAGCCGAGAUUGUGCCACUG1445 UGAGCCGAGAUUGUGCCACU 1446 GUGAGCCGAGAUUGUGCCAC 1447AGUGAGCCGAGAUUGUGCCA 1448 CAGUGAGCCGAGAUUGUGCC 1449 GCAGUGAGCCGAGAUUGUGC1450 UGCAGUGAGCCGAGAUUGUG 1451 UUGCAGUGAGCCGAGAUUGU 1452GUUGCAGUGAGCCGAGAUUG 1453 GGUUGCAGUGAGCCGAGAUU 1454 AGGUUGCAGUGAGCCGAGAU1455 GAGGUUGCAGUGAGCCGAGA 1456 UGGAGGUUGCAGUGAGCCGA 1457AGGUGGAGGUUGCAGUGAGC 1458 GAGGUGGAGGUUGCAGUGAG 1459 GGAGGUGGAGGUUGCAGUGA1460 UGGGAGGUGGAGGUUGCAGU 1461 UCCCAGCUACUCAGGAGGCU 1462AGUCCCAGCUACUCAGGAGG 1463 UAGUCCCAGCUACUCAGGAG 1464 AAAUAGCUGGGCAUGGUGGC1465 AAAAUAGCUGGGCAUGGUGG 1466 GCAGGCGGAUCACCUCAAGU 1467AGGCAGGCGGAUCACCUCAA 1468 AAGGCAGGCGGAUCACCUCA 1469 CUGUAAUCCCAGCACUUUGG1470 CCUGUAAUCCCAGCACUUUG 1471 ACCUGUAAUCCCAGCACUUU 1472GACCUGUAAUCCCAGCACUU 1473 AGACCUGUAAUCCCAGCACU 1474 CAGACCUGUAAUCCCAGCAC1475 UCAGACCUGUAAUCCCAGCA 1476 CUCAGACCUGUAAUCCCAGC 1477AGGCACAGUGGCUCAGACCU 1478 UAGGCACAGUGGCUCAGACC 1479 UUAGGCACAGUGGCUCAGAC1480 GUUAGGCACAGUGGCUCAGA 1481 GGUUAGGCACAGUGGCUCAG 1482AGGUUAGGCACAGUGGCUCA 1483 AUUAGGUUAGGCACAGUGGC 1484 GUCAUUAGGUUAGGCACAGU1485 AGUCAUUAGGUUAGGCACAG 1486 AAGUCAUUAGGUUAGGCACA 1487AAAGUCAUUAGGUUAGGCAC 1488 GAACACCUUACUUUCUUCUC 1489 AGCUCUCUUAGAACACCUUA1490 GGUGCCCAGCAAGAAGAGCU 1491 GGUUUAAGCGGUCUUCCGGC 1492GGGUUUAAGCGGUCUUCCGG 1493 UGGGUUUAAGCGGUCUUCCG 1494 CUGGGUUUAAGCGGUCUUCC1495 CAUAGCCUCGAACUCCUGGG 1496 UCAUAGCCUCGAACUCCUGG 1497AUCAUAGCCUCGAACUCCUG 1498 GAUCAUAGCCUCGAACUCCU 1499 GCAGAGGCUAUUCACAAGUG1500 UGCAGAGGCUAUUCACAAGU 1501 GUGCAGAGGCUAUUCACAAG 1502AGUGCAGAGGCUAUUCACAA 1503 AGGCUGGAGUGCAGAGGCUA 1504 UUUGCCCAGGCUGGAGUGCA1505 AUUUGCCCAGGCUGGAGUGC 1506 UAUUUGCCCAGGCUGGAGUG 1507CUAUUUGCCCAGGCUGGAGU 1508 ACUAUUUGCCCAGGCUGGAG 1509 CCAGAGGAGCUAUUUAUGUA1510 AGACUAAUGGGCACUGAAAA 1511 GACCAGACUAAUGGGCACUG 1512CAGACCAGACUAAUGGGCAC 1513 GUCAGACCAGACUAAUGGGC 1514 CCAGCUCAGUCAGACCAGAC1515 CCCAGCUCAGUCAGACCAGA 1516 GACCCAGCUCAGUCAGACCA 1517AGACCCAGCUCAGUCAGACC 1518 AGAGACCCAGCUCAGUCAGA 1519 UCAGAGACCCAGCUCAGUCA1520 UGACCCAGGCUAGUUAUCCC 1521 UUGACCCAGGCUAGUUAUCC 1522UUUGACCCAGGCUAGUUAUC 1523 CUUUGACCCAGGCUAGUUAU 1524 ACUUUGACCCAGGCUAGUUA1525 GACUUUGACCCAGGCUAGUU 1526 GGACUUUGACCCAGGCUAGU 1527UUCAGUCUGAGGGUCAAGGG 1528 GUUCAGUCUGAGGGUCAAGG 1529 UGUUCAGUCUGAGGGUCAAG1530 CUGUUCAGUCUGAGGGUCAA 1531 ACUGUUCAGUCUGAGGGUCA 1532AACUGUUCAGUCUGAGGGUC 1533 UAACUGUUCAGUCUGAGGGU 1534 UUAACUGUUCAGUCUGAGGG1535 GUGGAAGGUCAGUGGGUUAA 1536 GUGUGGAAGGUCAGUGGGUU 1537GGUGUGGAAGGUCAGUGGGU 1538 UGGGUGUGGAAGGUCAGUGG 1539 UUGGGUGUGGAAGGUCAGUG1540 UCUGCUUCCAAGAACCACCC 1541 GCUCUGCUUCCAAGAACCAC 1542AGCUCUGCUUCCAAGAACCA 1543 UAGCUCUGCUUCCAAGAACC 1544 CCUAGCUCUGCUUCCAAGAA1545 ACAUCCUAGCUCUGCUUCCA 1546 ACCUCCCACAUCCUAGCUCU 1547GACCUCCCACAUCCUAGCUC 1548 AGACCUCCCACAUCCUAGCU 1549 CAGACCUCCCACAUCCUAGC1550 GCAGACCUCCCACAUCCUAG 1551 GGCAGACCUCCCACAUCCUA 1552AGGCAGACCUCCCACAUCCU 1553 ACAGGCAGACCUCCCACAUC 1554 CACAGGCAGACCUCCCACAU1555 GGAGGAAGCAUGACAAGGAA 1556 AAGAGGAGGAAGCAUGACAA 1557GGGCAGCAUUUCAGUCUCUG 1558 GAUUUGCAUUGCCAUCGUGA 1559 AGAUUUGCAUUGCCAUCGUG1560 CUCUUUAGAUUUGCAUUGCC 1561 CCUCUUUAGAUUUGCAUUGC 1562GCCUCUUUAGAUUUGCAUUG 1563 AAGUGCCCUGCCUCUUUAGA 1564 GAAGUGCCCUGCCUCUUUAG1565 GGGAAGUGCCCUGCCUCUUU 1566 ACUGCCUGACAGGGAAGUGC 1567UCGGAGUCGAAGCAGAAGAG 1611 CUCGGAGUCGAAGCAGAAGA 1612 GCUCGGAGUCGAAGCAGAAG1613 CGCUCGGAGUCGAAGCAGAA 1614 ACAUGACACCCGCUCGGAGU 1615ACACAUGACACCCGCUCGGA 1616 UCACACAUGACACCCGCUCG 1617 CUCACACAUGACACCCGCUC1618 UCUCACACAUGACACCCGCU 1619 UUCUCACACAUGACACCCGC 1620GUACUGCCUGACAGGGAAGU 1568 GGUACUGCCUGACAGGGAAG 1569 CGGUACUGCCUGACAGGGAA1570 UAUGCCCAGCGGUACUGCCU 1571 UGCUAUGCCCAGCGGUACUG 1572UUGCUAUGCCCAGCGGUACU 1573 GUUGCUAUGCCCAGCGGUAC 1574 GGUUGCUAUGCCCAGCGGUA1575 AGGUUGCUAUGCCCAGCGGU 1576 AGAGGUUGCUAUGCCCAGCG 1577AGAGGCAGAGGUUGCUAUGC 1578 GAGAGGCAGAGGUUGCUAUG 1579 GGAGAGGCAGAGGUUGCUAU1580 CGGAGAGGCAGAGGUUGCUA 1581 AACGGAGAGGCAGAGGUUGC 1582GAGAAACGGAGAGGCAGAGG 1583 UGAGAAACGGAGAGGCAGAG 1584 UCUGAGAAACGGAGAGGCAG1585 AGGAGGUGGAUAUGUGAGCU 1586 CCCAGGAGGUGGAUAUGUGA 1587AGCCCAGGAGGUGGAUAUGU 1588 AAGCCCAGGAGGUGGAUAUG 1589 AAAGCCCAGGAGGUGGAUAU1590 AAAAGCCCAGGAGGUGGAUA 1591 UAAAAGCCCAGGAGGUGGAU 1592UUAAAAGCCCAGGAGGUGGA 1593 GCCCACUUAAAAGCCCAGGA 1594 AGCCCACUUAAAAGCCCAGG1595 AAGCCCACUUAAAAGCCCAG 1596 AAAGCCCACUUAAAAGCCCA 1597UAAAGCCCACUUAAAAGCCC 1598 CUAAAGCCCACUUAAAAGCC 1599 CACUAAAGCCCACUUAAAAG1600 CCUCACUAAAGCCCACUUAA 1601 CCCUCACUAAAGCCCACUUA 1602GGAGCCCAGUUGAAGGAGGA 1603 AGGAGCCCAGUUGAAGGAGG 1604 GGAGGAGCCCAGUUGAAGGA1605 AGGAGGAGCCCAGUUGAAGG 1606 AGUCGAAGCAGAAGAGCUGG 1607GAGUCGAAGCAGAAGAGCUG 1608 GGAGUCGAAGCAGAAGAGCU 1609 CGGAGUCGAAGCAGAAGAGC1610 GUUCUCACACAUGACACCCG 1621 CGUUCUCACACAUGACACCC 1622UGGCCGUUCUCACACAUGAC 1623 CUGGCCGUUCUCACACAUGA 1624 GCUGGCCGUUCUCACACAUG1625 UGCUGGCCGUUCUCACACAU 1626 CUGCUGGCCGUUCUCACACA 1627UCUGCUGGCCGUUCUCACAC 1628 CUCUGCUGGCCGUUCUCACA 1629

In some embodiments, the siRNA molecules comprise or consist of thenucleotide sequences (sense and antisense strands) shown in Table 3.

TABLE 3 SEQ SEQ ID ID Sense Sequence NO: Antisense Sequence NO:GUAGCCAGACAUGAGCUGU 1630 ACAGCUCAUGUCUGGCUAC 1631 AGACAUGAGCUGUGAGGGU1632 ACCCUCACAGCUCAUGUCU 1633 AUGAGCUGUGAGGGUCAAG 1634CUUGACCCUCACAGCUCAU 1635 UGAGCUGUGAGGGUCAAGC 1636 GCUUGACCCUCACAGCUCA1637 GAGCUGUGAGGGUCAAGCA 1638 UGCUUGACCCUCACAGCUC 1639AGCUGUGAGGGUCAAGCAC 1640 GUGCUUGACCCUCACAGCU 1641 GUGAGGGUCAAGCACAGCU1642 AGCUGUGCUUGACCCUCAC 1643 UGAGGGUCAAGCACAGCUA 1644UAGCUGUGCUUGACCCUCA 1645 GAGGGUCAAGCACAGCUAU 1646 AUAGCUGUGCUUGACCCUC1647 AGGGUCAAGCACAGCUAUC 1648 GAUAGCUGUGCUUGACCCU 1649GGGUCAAGCACAGCUAUCC 1650 GGAUAGCUGUGCUUGACCC 1651 CAAGCACAGCUAUCCAUCA1652 UGAUGGAUAGCUGUGCUUG 1653 CACAGCUAUCCAUCAGAUG 1654CAUCUGAUGGAUAGCUGUG 1655 ACAGCUAUCCAUCAGAUGA 1656 UCAUCUGAUGGAUAGCUGU1657 CAGCUAUCCAUCAGAUGAU 1658 AUCAUCUGAUGGAUAGCUG 1659AGCUAUCCAUCAGAUGAUC 1660 GAUCAUCUGAUGGAUAGCU 1661 GCUAUCCAUCAGAUGAUCU1662 AGAUCAUCUGAUGGAUAGC 1663 CUAUCCAUCAGAUGAUCUA 1664UAGAUCAUCUGAUGGAUAG 1665 CAUCAGAUGAUCUACUUUC 1666 GAAAGUAGAUCAUCUGAUG1667 AGAUGAUCUACUUUCAGCC 1668 GGCUGAAAGUAGAUCAUCU 1669GAUCUACUUUCAGCCUUCC 1670 GGAAGGCUGAAAGUAGAUC 1671 AUCUACUUUCAGCCUUCCU1672 AGGAAGGCUGAAAGUAGAU 1673 CAAUAGAAGACAGGUGGCU 1674AGCCACCUGUCUUCUAUUG 1675 AAUAGAAGACAGGUGGCUG 1676 CAGCCACCUGUCUUCUAUU1677 CAGGUGGCUGUACCCUUGG 1678 CCAAGGGUACAGCCACCUG 1679AGGUGGCUGUACCCUUGGC 1680 GCCAAGGGUACAGCCACCU 1681 GGCUGUACCCUUGGCCAAG1682 CUUGGCCAAGGGUACAGCC 1683 UGGUGUCUGCUGUCACUGU 1684ACAGUGACAGCAGACACCA 1685 GUCUGCUGUCACUGUGCCC 1686 GGGCACAGUGACAGCAGAC1687 CUGCUGUCACUGUGCCCUC 1688 GAGGGCACAGUGACAGCAG 1689UGCUGUCACUGUGCCCUCA 1690 UGAGGGCACAGUGACAGCA 1691 GCUGUCACUGUGCCCUCAU1692 AUGAGGGCACAGUGACAGC 1693 CUGUCACUGUGCCCUCAUU 1694AAUGAGGGCACAGUGACAG 1695 UGUCACUGUGCCCUCAUUG 1696 CAAUGAGGGCACAGUGACA1697 GUCACUGUGCCCUCAUUGG 1698 CCAAUGAGGGCACAGUGAC 1699ACUGUGCCCUCAUUGGCCC 1700 GGGCCAAUGAGGGCACAGU 1701 CCCAGCAAUCAGACUCAAC1702 GUUGAGUCUGAUUGCUGGG 1703 GGAGCAACUGCCAUCCGAG 1704CUCGGAUGGCAGUUGCUCC 1705 GAGCAACUGCCAUCCGAGG 1706 CCUCGGAUGGCAGUUGCUC1707 AGCAACUGCCAUCCGAGGC 1708 GCCUCGGAUGGCAGUUGCU 1709GCAACUGCCAUCCGAGGCU 1710 AGCCUCGGAUGGCAGUUGC 1711 CAACUGCCAUCCGAGGCUC1712 GAGCCUCGGAUGGCAGUUG 1713 GCCAUCCGAGGCUCCUGAA 1714UUCAGGAGCCUCGGAUGGC 1715 AACCAGGGCCAUUCACCAG 1716 CUGGUGAAUGGCCCUGGUU1717 ACCAGGGCCAUUCACCAGG 1718 CCUGGUGAAUGGCCCUGGU 1719CCAGGGCCAUUCACCAGGA 1720 UCCUGGUGAAUGGCCCUGG 1721 CAGGGCCAUUCACCAGGAG1722 CUCCUGGUGAAUGGCCCUG 1723 GGCCAUUCACCAGGAGCAU 1724AUGCUCCUGGUGAAUGGCC 1725 GCCAUUCACCAGGAGCAUG 1726 CAUGCUCCUGGUGAAUGGC1727 CCAUUCACCAGGAGCAUGC 1728 GCAUGCUCCUGGUGAAUGG 1729CAUUCACCAGGAGCAUGCG 1730 CGCAUGCUCCUGGUGAAUG 1731 AUUCACCAGGAGCAUGCGG1732 CCGCAUGCUCCUGGUGAAU 1733 UUCACCAGGAGCAUGCGGC 1734GCCGCAUGCUCCUGGUGAA 1735 UCACCAGGAGCAUGCGGCU 1736 AGCCGCAUGCUCCUGGUGA1737 AGCAUGCGGCUCCCUGAUG 1738 CAUCAGGGAGCCGCAUGCU 1739GCAUGCGGCUCCCUGAUGU 1740 ACAUCAGGGAGCCGCAUGC 1741 CAUGCGGCUCCCUGAUGUC1742 GACAUCAGGGAGCCGCAUG 1743 AUGCGGCUCCCUGAUGUCC 1744GGACAUCAGGGAGCCGCAU 1745 UGCGGCUCCCUGAUGUCCA 1746 UGGACAUCAGGGAGCCGCA1747 GCUCCCUGAUGUCCAGCUC 1748 GAGCUGGACAUCAGGGAGC 1749CUCCCUGAUGUCCAGCUCU 1750 AGAGCUGGACAUCAGGGAG 1751 UCCCUGAUGUCCAGCUCUG1752 CAGAGCUGGACAUCAGGGA 1753 CCCUGAUGUCCAGCUCUGG 1754CCAGAGCUGGACAUCAGGG 1755 CCUGAUGUCCAGCUCUGGC 1756 GCCAGAGCUGGACAUCAGG1757 CUGAUGUCCAGCUCUGGCU 1758 AGCCAGAGCUGGACAUCAG 1759UCUGGUGCUGGAGCUAGCC 1760 GGCUAGCUCCAGCACCAGA 1761 UGGUGCUGGAGCUAGCCAA1762 UUGGCUAGCUCCAGCACCA 1763 GGUGCUGGAGCUAGCCAAG 1764CUUGGCUAGCUCCAGCACC 1765 GUGCUGGAGCUAGCCAAGC 1766 GCUUGGCUAGCUCCAGCAC1767 GCUGGAGCUAGCCAAGCAG 1768 CUGCUUGGCUAGCUCCAGC 1769CUGGAGCUAGCCAAGCAGC 1770 GCUGCUUGGCUAGCUCCAG 1771 UGGAGCUAGCCAAGCAGCA1772 UGCUGCUUGGCUAGCUCCA 1773 GGAGCUAGCCAAGCAGCAA 1774UUGCUGCUUGGCUAGCUCC 1775 GAGCUAGCCAAGCAGCAAA 1776 UUUGCUGCUUGGCUAGCUC1777 AGCUAGCCAAGCAGCAAAU 1778 AUUUGCUGCUUGGCUAGCU 1779GCUAGCCAAGCAGCAAAUC 1780 GAUUUGCUGCUUGGCUAGC 1781 CAGCAAAUCCUGGAUGGGU1782 ACCCAUCCAGGAUUUGCUG 1783 AGCAAAUCCUGGAUGGGUU 1784AACCCAUCCAGGAUUUGCU 1785 GCAAAUCCUGGAUGGGUUG 1786 CAACCCAUCCAGGAUUUGC1787 CAAAUCCUGGAUGGGUUGC 1788 GCAACCCAUCCAGGAUUUG 1789AAAUCCUGGAUGGGUUGCA 1790 UGCAACCCAUCCAGGAUUU 1791 GGUUGCACCUGACCAGUCG1792 CGACUGGUCAGGUGCAACC 1793 GUUGCACCUGACCAGUCGU 1794ACGACUGGUCAGGUGCAAC 1795 UUGCACCUGACCAGUCGUC 1796 GACGACUGGUCAGGUGCAA1797 UGCACCUGACCAGUCGUCC 1798 GGACGACUGGUCAGGUGCA 1799UGACCAGUCGUCCCAGAAU 1800 AUUCUGGGACGACUGGUCA 1801 GACCAGUCGUCCCAGAAUA1802 UAUUCUGGGACGACUGGUC 1803 ACCAGUCGUCCCAGAAUAA 1804UUAUUCUGGGACGACUGGU 1805 CCAGUCGUCCCAGAAUAAC 1806 GUUAUUCUGGGACGACUGG1807 CAGUCGUCCCAGAAUAACU 1808 AGUUAUUCUGGGACGACUG 1809AGUCGUCCCAGAAUAACUC 1810 GAGUUAUUCUGGGACGACU 1811 GUCGUCCCAGAAUAACUCA1812 UGAGUUAUUCUGGGACGAC 1813 UCGUCCCAGAAUAACUCAU 1814AUGAGUUAUUCUGGGACGA 1815 CGUCCCAGAAUAACUCAUC 1816 GAUGAGUUAUUCUGGGACG1817 GUCCCAGAAUAACUCAUCC 1818 GGAUGAGUUAUUCUGGGAC 1819UCCCAGAAUAACUCAUCCU 1820 AGGAUGAGUUAUUCUGGGA 1821 CCCAGAAUAACUCAUCCUC1822 GAGGAUGAGUUAUUCUGGG 1823 GACUACAGCCAGGGAGUGU 1824ACACUCCCUGGCUGUAGUC 1825 ACUACAGCCAGGGAGUGUG 1826 CACACUCCCUGGCUGUAGU1827 CUACAGCCAGGGAGUGUGG 1828 CCACACUCCCUGGCUGUAG 1829GAGUGUGGCUCCAGGGAAU 1830 AUUCCCUGGAGCCACACUC 1831 GGGAGGAGGUCAUCAGCUU1832 AAGCUGAUGACCUCCUCCC 1833 GAGGUCAUCAGCUUUGCUA 1834UAGCAAAGCUGAUGACCUC 1835 AGGUCAUCAGCUUUGCUAC 1836 GUAGCAAAGCUGAUGACCU1837 GGUCAUCAGCUUUGCUACU 1838 AGUAGCAAAGCUGAUGACC 1839GCUUUGCUACUGUCACAGA 1840 UCUGUGACAGUAGCAAAGC 1841 CUUUGCUACUGUCACAGAC1842 GUCUGUGACAGUAGCAAAG 1843 UUUGCUACUGUCACAGACU 1844AGUCUGUGACAGUAGCAAA 1845 UUGCUACUGUCACAGACUC 1846 GAGUCUGUGACAGUAGCAA1847 UGCUACUGUCACAGACUCC 1848 GGAGUCUGUGACAGUAGCA 1849ACUGUCACAGACUCCACUU 1850 AAGUGGAGUCUGUGACAGU 1851 CUGUCACAGACUCCACUUC1852 GAAGUGGAGUCUGUGACAG 1853 UGUCACAGACUCCACUUCA 1854UGAAGUGGAGUCUGUGACA 1855 GUCACAGACUCCACUUCAG 1856 CUGAAGUGGAGUCUGUGAC1857 UCACAGACUCCACUUCAGC 1858 GCUGAAGUGGAGUCUGUGA 1859CACAGACUCCACUUCAGCC 1860 GGCUGAAGUGGAGUCUGUG 1861 UCCACUUCAGCCUACAGCU1862 AGCUGUAGGCUGAAGUGGA 1863 CCACUUCAGCCUACAGCUC 1864GAGCUGUAGGCUGAAGUGG 1865 CACUUCAGCCUACAGCUCC 1866 GGAGCUGUAGGCUGAAGUG1867 ACUUCAGCCUACAGCUCCC 1868 GGGAGCUGUAGGCUGAAGU 1869CCUACAGCUCCCUGCUCAC 1870 GUGAGCAGGGAGCUGUAGG 1871 CUACAGCUCCCUGCUCACU1872 AGUGAGCAGGGAGCUGUAG 1873 UACAGCUCCCUGCUCACUU 1874AAGUGAGCAGGGAGCUGUA 1875 GCUCCCUGCUCACUUUUCA 1876 UGAAAAGUGAGCAGGGAGC1877 CUCCCUGCUCACUUUUCAC 1878 GUGAAAAGUGAGCAGGGAG 1879GCUCACUUUUCACCUGUCC 1880 GGACAGGUGAAAAGUGAGC 1881 CUCACUUUUCACCUGUCCA1882 UGGACAGGUGAAAAGUGAG 1883 UGUCCACUCCUCGGUCCCA 1884UGGGACCGAGGAGUGGACA 1885 UCGGUCCCACCACCUGUAC 1886 GUACAGGUGGUGGGACCGA1887 CCACCACCUGUACCAUGCC 1888 GGCAUGGUACAGGUGGUGG 1889CACCACCUGUACCAUGCCC 1890 GGGCAUGGUACAGGUGGUG 1891 ACCACCUGUACCAUGCCCG1892 CGGGCAUGGUACAGGUGGU 1893 CACCCUUCCUGGCACUCUU 1894AAGAGUGCCAGGAAGGGUG 1895 ACCCUUCCUGGCACUCUUU 1896 AAAGAGUGCCAGGAAGGGU1897 CCCUUCCUGGCACUCUUUG 1898 CAAAGAGUGCCAGGAAGGG 1899CCUUCCUGGCACUCUUUGC 1900 GCAAAGAGUGCCAGGAAGG 1901 UUCCUGGCACUCUUUGCUU1902 AAGCAAAGAGUGCCAGGAA 1903 UCCUGGCACUCUUUGCUUG 1904CAAGCAAAGAGUGCCAGGA 1905 CCUGGCACUCUUUGCUUGA 1906 UCAAGCAAAGAGUGCCAGG1907 CUGGCACUCUUUGCUUGAG 1908 CUCAAGCAAAGAGUGCCAG 1909UGGCACUCUUUGCUUGAGG 1910 CCUCAAGCAAAGAGUGCCA 1911 GGCACUCUUUGCUUGAGGA1912 UCCUCAAGCAAAGAGUGCC 1913 GCACUCUUUGCUUGAGGAU 1914AUCCUCAAGCAAAGAGUGC 1915 CACUCUUUGCUUGAGGAUC 1916 GAUCCUCAAGCAAAGAGUG1917 ACUCUUUGCUUGAGGAUCU 1918 AGAUCCUCAAGCAAAGAGU 1919CUCUUUGCUUGAGGAUCUU 1920 AAGAUCCUCAAGCAAAGAG 1921 UCUUUGCUUGAGGAUCUUC1922 GAAGAUCCUCAAGCAAAGA 1923 UGCUUGAGGAUCUUCCGAU 1924AUCGGAAGAUCCUCAAGCA 1925 GCUUGAGGAUCUUCCGAUG 1926 CAUCGGAAGAUCCUCAAGC1927 GCACUCUCCUGGCUGAGCA 1928 UGCUCAGCCAGGAGAGUGC 1929CUCCUGGCUGAGCACCACA 1930 UGUGGUGCUCAGCCAGGAG 1931 UGGCUGAGCACCACAUCAC1932 GUGAUGUGGUGCUCAGCCA 1933 GGCUGAGCACCACAUCACC 1934GGUGAUGUGGUGCUCAGCC 1935 GCUGAGCACCACAUCACCA 1936 UGGUGAUGUGGUGCUCAGC1937 CUGAGCACCACAUCACCAA 1938 UUGGUGAUGUGGUGCUCAG 1939CCAACCUGGGCUGGCAUAC 1940 GUAUGCCAGCCCAGGUUGG 1941 CAACCUGGGCUGGCAUACC1942 GGUAUGCCAGCCCAGGUUG 1943 AACCUGGGCUGGCAUACCU 1944AGGUAUGCCAGCCCAGGUU 1945 ACCUGGGCUGGCAUACCUU 1946 AAGGUAUGCCAGCCCAGGU1947 CCUGGGCUGGCAUACCUUA 1948 UAAGGUAUGCCAGCCCAGG 1949CUGGGCUGGCAUACCUUAA 1950 UUAAGGUAUGCCAGCCCAG 1951 UGGGCUGGCAUACCUUAAC1952 GUUAAGGUAUGCCAGCCCA 1953 GGGCUGGCAUACCUUAACU 1954AGUUAAGGUAUGCCAGCCC 1955 GGCUGGCAUACCUUAACUC 1956 GAGUUAAGGUAUGCCAGCC1957 GCUGGCAUACCUUAACUCU 1958 AGAGUUAAGGUAUGCCAGC 1959CAUACCUUAACUCUGCCCU 1960 AGGGCAGAGUUAAGGUAUG 1961 AUACCUUAACUCUGCCCUC1962 GAGGGCAGAGUUAAGGUAU 1963 UACCUUAACUCUGCCCUCU 1964AGAGGGCAGAGUUAAGGUA 1965 UCUGCCCUCUAGUGGCUUG 1966 CAAGCCACUAGAGGGCAGA1967 CUGCCCUCUAGUGGCUUGA 1968 UCAAGCCACUAGAGGGCAG 1969UGCCCUCUAGUGGCUUGAG 1970 CUCAAGCCACUAGAGGGCA 1971 AGAAGUCUGGUGUCCUGAA1972 UUCAGGACACCAGACUUCU 1973 CAGGACACCAGCAGCCCUU 1974AAGGGCUGCUGGUGUCCUG 1975 AGGACACCAGCAGCCCUUC 1976 GAAGGGCUGCUGGUGUCCU1977 ACACCAGCAGCCCUUCCUA 1978 UAGGAAGGGCUGCUGGUGU 1979CACCAGCAGCCCUUCCUAG 1980 CUAGGAAGGGCUGCUGGUG 1981 ACCAGCAGCCCUUCCUAGA1982 UCUAGGAAGGGCUGCUGGU 1983 CCAGCAGCCCUUCCUAGAG 1984CUCUAGGAAGGGCUGCUGG 1985 CAGCAGCCCUUCCUAGAGC 1986 GCUCUAGGAAGGGCUGCUG1987 AGCAGCCCUUCCUAGAGCU 1988 AGCUCUAGGAAGGGCUGCU 1989GCCCUUCCUAGAGCUUAAG 1990 CUUAAGCUCUAGGAAGGGC 1991 CCCUUCCUAGAGCUUAAGA1992 UCUUAAGCUCUAGGAAGGG 1993 AGCUUAAGAUCCGAGCCAA 1994UUGGCUCGGAUCUUAAGCU 1995 GCUUAAGAUCCGAGCCAAU 1996 AUUGGCUCGGAUCUUAAGC1997 CUUAAGAUCCGAGCCAAUG 1998 CAUUGGCUCGGAUCUUAAG 1999UUAAGAUCCGAGCCAAUGA 2000 UCAUUGGCUCGGAUCUUAA 2001 UAAGAUCCGAGCCAAUGAG2002 CUCAUUGGCUCGGAUCUUA 2003 CGAGCCAAUGAGCCUGGAG 2004CUCCAGGCUCAUUGGCUCG 2005 CCCUUAUGUUGCAGGCGAG 2006 CUCGCCUGCAACAUAAGGG2007 CAUUACGUAGACUUCCAGG 2008 CCUGGAAGUCUACGUAAUG 2009AUUACGUAGACUUCCAGGA 2010 UCCUGGAAGUCUACGUAAU 2011 UUACGUAGACUUCCAGGAA2012 UUCCUGGAAGUCUACGUAA 2013 ACUGGAUACUGCAGCCCGA 2014UCGGGCUGCAGUAUCCAGU 2015 CUGGAUACUGCAGCCCGAG 2016 CUCGGGCUGCAGUAUCCAG2017 UGGAUACUGCAGCCCGAGG 2018 CCUCGGGCUGCAGUAUCCA 2019GGGUACCAGCUGAAUUACU 2020 AGUAAUUCAGCUGGUACCC 2021 CUGAAUUACUGCAGUGGGC2022 GCCCACUGCAGUAAUUCAG 2023 UGAAUUACUGCAGUGGGCA 2024UGCCCACUGCAGUAAUUCA 2025 UGGCAGCCCAGGCAUUGCU 2026 AGCAAUGCCUGGGCUGCCA2027 GCAUUGCUGCCUCUUUCCA 2028 UGGAAAGAGGCAGCAAUGC 2029CAUUGCUGCCUCUUUCCAU 2030 AUGGAAAGAGGCAGCAAUG 2031 AUUGCUGCCUCUUUCCAUU2032 AAUGGAAAGAGGCAGCAAU 2033 UGCUGCCUCUUUCCAUUCU 2034AGAAUGGAAAGAGGCAGCA 2035 GCUGCCUCUUUCCAUUCUG 2036 CAGAAUGGAAAGAGGCAGC2037 CUGCCUCUUUCCAUUCUGC 2038 GCAGAAUGGAAAGAGGCAG 2039UGCCUCUUUCCAUUCUGCC 2040 GGCAGAAUGGAAAGAGGCA 2041 GCCUCUUUCCAUUCUGCCG2042 CGGCAGAAUGGAAAGAGGC 2043 CCUCUUUCCAUUCUGCCGU 2044ACGGCAGAAUGGAAAGAGG 2045 CUCUUUCCAUUCUGCCGUC 2046 GACGGCAGAAUGGAAAGAG2047 CAUUCUGCCGUCUUCAGCC 2048 GGCUGAAGACGGCAGAAUG 2049CUUCAGCCUCCUCAAAGCC 2050 GGCUUUGAGGAGGCUGAAG 2051 UUCAGCCUCCUCAAAGCCA2052 UGGCUUUGAGGAGGCUGAA 2053 UCAGCCUCCUCAAAGCCAA 2054UUGGCUUUGAGGAGGCUGA 2055 CAGCCUCCUCAAAGCCAAC 2056 GUUGGCUUUGAGGAGGCUG2057 UCCUUGGCCUGCCAGUACC 2058 GGUACUGGCAGGCCAAGGA 2059CCUGCCAGUACCUCCUGUU 2060 AACAGGAGGUACUGGCAGG 2061 CUGCCAGUACCUCCUGUUG2062 CAACAGGAGGUACUGGCAG 2063 UGCCAGUACCUCCUGUUGU 2064ACAACAGGAGGUACUGGCA 2065 GCCAGUACCUCCUGUUGUG 2066 CACAACAGGAGGUACUGGC2067 CCAGUACCUCCUGUUGUGU 2068 ACACAACAGGAGGUACUGG 2069CAGUACCUCCUGUUGUGUC 2070 GACACAACAGGAGGUACUG 2071 GUACCUCCUGUUGUGUCCC2072 GGGACACAACAGGAGGUAC 2073 UACCUCCUGUUGUGUCCCU 2074AGGGACACAACAGGAGGUA 2075 ACCUCCUGUUGUGUCCCUA 2076 UAGGGACACAACAGGAGGU2077 CCUCCUGUUGUGUCCCUAC 2078 GUAGGGACACAACAGGAGG 2079CUCCUGUUGUGUCCCUACU 2080 AGUAGGGACACAACAGGAG 2081 UUGUGUCCCUACUGCCCGA2082 UCGGGCAGUAGGGACACAA 2083 UGUGUCCCUACUGCCCGAA 2084UUCGGGCAGUAGGGACACA 2085 GUGUCCCUACUGCCCGAAG 2086 CUUCGGGCAGUAGGGACAC2087 UGUCCCUACUGCCCGAAGG 2088 CCUUCGGGCAGUAGGGACA 2089UCUCUCUCCUCUACCUGGA 2090 UCCAGGUAGAGGAGAGAGA 2091 UCUCCUCUACCUGGAUCAU2092 AUGAUCCAGGUAGAGGAGA 2093 CUCCUCUACCUGGAUCAUA 2094UAUGAUCCAGGUAGAGGAG 2095 UCCUCUACCUGGAUCAUAA 2096 UUAUGAUCCAGGUAGAGGA2097 CCUCUACCUGGAUCAUAAU 2098 AUUAUGAUCCAGGUAGAGG 2099CUCUACCUGGAUCAUAAUG 2100 CAUUAUGAUCCAGGUAGAG 2101 UCUACCUGGAUCAUAAUGG2102 CCAUUAUGAUCCAGGUAGA 2103 CUACCUGGAUCAUAAUGGC 2104GCCAUUAUGAUCCAGGUAG 2105 UACCUGGAUCAUAAUGGCA 2106 UGCCAUUAUGAUCCAGGUA2107 ACCUGGAUCAUAAUGGCAA 2108 UUGCCAUUAUGAUCCAGGU 2109CCUGGAUCAUAAUGGCAAU 2110 AUUGCCAUUAUGAUCCAGG 2111 CUGGAUCAUAAUGGCAAUG2112 CAUUGCCAUUAUGAUCCAG 2113 UGGAUCAUAAUGGCAAUGU 2114ACAUUGCCAUUAUGAUCCA 2115 GGAUCAUAAUGGCAAUGUG 2116 CACAUUGCCAUUAUGAUCC2117 GAUCAUAAUGGCAAUGUGG 2118 CCACAUUGCCAUUAUGAUC 2119AUAAUGGCAAUGUGGUCAA 2120 UUGACCACAUUGCCAUUAU 2121 UAAUGGCAAUGUGGUCAAG2122 CUUGACCACAUUGCCAUUA 2123 AAUGGCAAUGUGGUCAAGA 2124UCUUGACCACAUUGCCAUU 2125 AAUGUGGUCAAGACGGAUG 2126 CAUCCGUCUUGACCACAUU2127 AUGUGGUCAAGACGGAUGU 2128 ACAUCCGUCUUGACCACAU 2129UGUGGUCAAGACGGAUGUG 2130 CACAUCCGUCUUGACCACA 2131 GUGGUCAAGACGGAUGUGC2132 GCACAUCCGUCUUGACCAC 2133 UGGUCAAGACGGAUGUGCC 2134GGCACAUCCGUCUUGACCA 2135 GGUCAAGACGGAUGUGCCA 2136 UGGCACAUCCGUCUUGACC2137 GUCAAGACGGAUGUGCCAG 2138 CUGGCACAUCCGUCUUGAC 2139UCAAGACGGAUGUGCCAGA 2140 UCUGGCACAUCCGUCUUGA 2141 CAAGACGGAUGUGCCAGAU2142 AUCUGGCACAUCCGUCUUG 2143 AAGACGGAUGUGCCAGAUA 2144UAUCUGGCACAUCCGUCUU 2145 AGACGGAUGUGCCAGAUAU 2146 AUAUCUGGCACAUCCGUCU2147 GACGGAUGUGCCAGAUAUG 2148 CAUAUCUGGCACAUCCGUC 2149ACGGAUGUGCCAGAUAUGG 2150 CCAUAUCUGGCACAUCCGU 2151 CGGAUGUGCCAGAUAUGGU2152 ACCAUAUCUGGCACAUCCG 2153 GGAUGUGCCAGAUAUGGUG 2154CACCAUAUCUGGCACAUCC 2155 GAUGUGCCAGAUAUGGUGG 2156 CCACCAUAUCUGGCACAUC2157 GCCAGAUAUGGUGGUGGAG 2158 CUCCACCACCAUAUCUGGC 2159CCAGAUAUGGUGGUGGAGG 2160 CCUCCACCACCAUAUCUGG 2161 CAGAUAUGGUGGUGGAGGC2162 GCCUCCACCACCAUAUCUG 2163 AGAUAUGGUGGUGGAGGCC 2164GGCCUCCACCACCAUAUCU 2165 GAUAUGGUGGUGGAGGCCU 2166 AGGCCUCCACCACCAUAUC2167 AUAUGGUGGUGGAGGCCUG 2168 CAGGCCUCCACCACCAUAU 2169CCUGUGGCUGCAGCUAGCA 2170 UGCUAGCUGCAGCCACAGG 2171 UGUGGCUGCAGCUAGCAAG2172 CUUGCUAGCUGCAGCCACA 2173 GUGGCUGCAGCUAGCAAGA 2174UCUUGCUAGCUGCAGCCAC 2175 UGGCUGCAGCUAGCAAGAG 2176 CUCUUGCUAGCUGCAGCCA2177 GGCUGCAGCUAGCAAGAGG 2178 CCUCUUGCUAGCUGCAGCC 2179CUGCAGCUAGCAAGAGGAC 2180 GUCCUCUUGCUAGCUGCAG 2181 CAGCUAGCAAGAGGACCUG2182 CAGGUCCUCUUGCUAGCUG 2183 GCUAGCAAGAGGACCUGGG 2184CCCAGGUCCUCUUGCUAGC 2185 AGACCAAGAUGAAGUUUCC 2186 GGAAACUUCAUCUUGGUCU2187 UGAAGUUUCCCAGGCACAG 2188 CUGUGCCUGGGAAACUUCA 2189GAAGUUUCCCAGGCACAGG 2190 CCUGUGCCUGGGAAACUUC 2191 UCCCAGGCACAGGGCAUCU2192 AGAUGCCCUGUGCCUGGGA 2193 GGCAUCUGUGACUGGAGGC 2194GCCUCCAGUCACAGAUGCC 2195 GCAUCUGUGACUGGAGGCA 2196 UGCCUCCAGUCACAGAUGC2197 CAACCACCUGGCAAUAUGA 2198 UCAUAUUGCCAGGUGGUUG 2199AACCACCUGGCAAUAUGAC 2200 GUCAUAUUGCCAGGUGGUU 2201 ACCACCUGGCAAUAUGACU2202 AGUCAUAUUGCCAGGUGGU 2203 CCACCUGGCAAUAUGACUC 2204GAGUCAUAUUGCCAGGUGG 2205 CACCUGGCAAUAUGACUCA 2206 UGAGUCAUAUUGCCAGGUG2207 ACCUGGCAAUAUGACUCAC 2208 GUGAGUCAUAUUGCCAGGU 2209CCUGGCAAUAUGACUCACU 2210 AGUGAGUCAUAUUGCCAGG 2211 CUGGCAAUAUGACUCACUU2212 AAGUGAGUCAUAUUGCCAG 2213 UGGCAAUAUGACUCACUUG 2214CAAGUGAGUCAUAUUGCCA 2215 AAUAUGACUCACUUGACCC 2216 GGGUCAAGUGAGUCAUAUU2217 CCCUAUGGGACCCAAAUGG 2218 CCAUUUGGGUCCCAUAGGG 2219CCUAUGGGACCCAAAUGGG 2220 CCCAUUUGGGUCCCAUAGG 2221 CUAUGGGACCCAAAUGGGC2222 GCCCAUUUGGGUCCCAUAG 2223 UAUGGGACCCAAAUGGGCA 2224UGCCCAUUUGGGUCCCAUA 2225 AUGGGACCCAAAUGGGCAC 2226 GUGCCCAUUUGGGUCCCAU2227 CCCAAAUGGGCACUUUCUU 2228 AAGAAAGUGCCCAUUUGGG 2229CCAAAUGGGCACUUUCUUG 2230 CAAGAAAGUGCCCAUUUGG 2231 CAAAUGGGCACUUUCUUGU2232 ACAAGAAAGUGCCCAUUUG 2233 AAAUGGGCACUUUCUUGUC 2234GACAAGAAAGUGCCCAUUU 2235 AAUGGGCACUUUCUUGUCU 2236 AGACAAGAAAGUGCCCAUU2237 UGGGCACUUUCUUGUCUGA 2238 UCAGACAAGAAAGUGCCCA 2239GGGCACUUUCUUGUCUGAG 2240 CUCAGACAAGAAAGUGCCC 2241 UGGCUUAUUCCAGGUUGGC2242 GCCAACCUGGAAUAAGCCA 2243 GGCUUAUUCCAGGUUGGCU 2244AGCCAACCUGGAAUAAGCC 2245 GCUUAUUCCAGGUUGGCUG 2246 CAGCCAACCUGGAAUAAGC2247 CUUAUUCCAGGUUGGCUGA 2248 UCAGCCAACCUGGAAUAAG 2249UUCCAGGUUGGCUGAUGUG 2250 CACAUCAGCCAACCUGGAA 2251 UCCAGGUUGGCUGAUGUGU2252 ACACAUCAGCCAACCUGGA 2253 CCAGGUUGGCUGAUGUGUU 2254AACACAUCAGCCAACCUGG 2255 CAGGUUGGCUGAUGUGUUG 2256 CAACACAUCAGCCAACCUG2257 AGGUUGGCUGAUGUGUUGG 2258 CCAACACAUCAGCCAACCU 2259GGUUGGCUGAUGUGUUGGG 2260 CCCAACACAUCAGCCAACC 2261 AGAUGGGUAAAGCGUUUCU2262 AGAAACGCUUUACCCAUCU 2263 GAUGGGUAAAGCGUUUCUU 2264AAGAAACGCUUUACCCAUC 2265 AUGGGUAAAGCGUUUCUUC 2266 GAAGAAACGCUUUACCCAU2267 UGGGUAAAGCGUUUCUUCU 2268 AGAAGAAACGCUUUACCCA 2269GGGUAAAGCGUUUCUUCUA 2270 UAGAAGAAACGCUUUACCC 2271 GGUAAAGCGUUUCUUCUAA2272 UUAGAAGAAACGCUUUACC 2273 GUAAAGCGUUUCUUCUAAA 2274UUUAGAAGAAACGCUUUAC 2275 UAAAGCGUUUCUUCUAAAG 2276 CUUUAGAAGAAACGCUUUA2277 AAAGCGUUUCUUCUAAAGG 2278 CCUUUAGAAGAAACGCUUU 2279AAGCGUUUCUUCUAAAGGG 2280 CCCUUUAGAAGAAACGCUU 2281 AAAGCAUGAUUUCCUGCCC2282 GGGCAGGAAAUCAUGCUUU 2283 AAGCAUGAUUUCCUGCCCU 2284AGGGCAGGAAAUCAUGCUU 2285 AGCAUGAUUUCCUGCCCUA 2286 UAGGGCAGGAAAUCAUGCU2287 GCAUGAUUUCCUGCCCUAA 2288 UUAGGGCAGGAAAUCAUGC 2289CAUGAUUUCCUGCCCUAAG 2290 CUUAGGGCAGGAAAUCAUG 2291 AUGAUUUCCUGCCCUAAGU2292 ACUUAGGGCAGGAAAUCAU 2293 UGAUUUCCUGCCCUAAGUC 2294GACUUAGGGCAGGAAAUCA 2295 GAUUUCCUGCCCUAAGUCC 2296 GGACUUAGGGCAGGAAAUC2297 AUUUCCUGCCCUAAGUCCU 2298 AGGACUUAGGGCAGGAAAU 2299UUUCCUGCCCUAAGUCCUG 2300 CAGGACUUAGGGCAGGAAA 2301 UUCCUGCCCUAAGUCCUGU2302 ACAGGACUUAGGGCAGGAA 2303 UCCUGCCCUAAGUCCUGUG 2304CACAGGACUUAGGGCAGGA 2305 AGAAGAUGUCAGGGACUAG 2306 CUAGUCCCUGACAUCUUCU2307 GAAGAUGUCAGGGACUAGG 2308 CCUAGUCCCUGACAUCUUC 2309AAGAUGUCAGGGACUAGGG 2310 CCCUAGUCCCUGACAUCUU 2311 AGAUGUCAGGGACUAGGGA2312 UCCCUAGUCCCUGACAUCU 2313 GUCAGGGACUAGGGAGGGA 2314UCCCUCCCUAGUCCCUGAC 2315 UACUUAGCCUCUCCCAAGA 2316 UCUUGGGAGAGGCUAAGUA2317 AGGAGGAAGCAGAUAGAUG 2318 CAUCUAUCUGCUUCCUCCU 2319GGAGGAAGCAGAUAGAUGG 2320 CCAUCUAUCUGCUUCCUCC 2321 GAGGAAGCAGAUAGAUGGU2322 ACCAUCUAUCUGCUUCCUC 2323 AGGAAGCAGAUAGAUGGUC 2324GACCAUCUAUCUGCUUCCU 2325 GGAAGCAGAUAGAUGGUCC 2326 GGACCAUCUAUCUGCUUCC2327 GAAGCAGAUAGAUGGUCCA 2328 UGGACCAUCUAUCUGCUUC 2329UAGAUGGUCCAGCAGGCUU 2330 AAGCCUGCUGGACCAUCUA 2331 AGAUGGUCCAGCAGGCUUG2332 CAAGCCUGCUGGACCAUCU 2333 GAUGGUCCAGCAGGCUUGA 2334UCAAGCCUGCUGGACCAUC 2335 AUGGUCCAGCAGGCUUGAA 2336 UUCAAGCCUGCUGGACCAU2337 UGGUCCAGCAGGCUUGAAG 2338 CUUCAAGCCUGCUGGACCA 2339GGUCCAGCAGGCUUGAAGC 2340 GCUUCAAGCCUGCUGGACC 2341 GUCCAGCAGGCUUGAAGCA2342 UGCUUCAAGCCUGCUGGAC 2343 UCCAGCAGGCUUGAAGCAG 2344CUGCUUCAAGCCUGCUGGA 2345 CCCAGGGUAAGGGCUGUUG 2346 CAACAGCCCUUACCCUGGG2347 GGGUAAGGGCUGUUGAGGU 2348 ACCUCAACAGCCCUUACCC 2349GGUAAGGGCUGUUGAGGUA 2350 UACCUCAACAGCCCUUACC 2351 GUAAGGGCUGUUGAGGUAC2352 GUACCUCAACAGCCCUUAC 2353 UAAGGGCUGUUGAGGUACC 2354GGUACCUCAACAGCCCUUA 2355 AAGGGCUGUUGAGGUACCU 2356 AGGUACCUCAACAGCCCUU2357 AGGGCUGUUGAGGUACCUU 2358 AAGGUACCUCAACAGCCCU 2359GGGCUGUUGAGGUACCUUA 2360 UAAGGUACCUCAACAGCCC 2361 GGCUGUUGAGGUACCUUAA2362 UUAAGGUACCUCAACAGCC 2363 GCUGUUGAGGUACCUUAAG 2364CUUAAGGUACCUCAACAGC 2365 CUGUUGAGGUACCUUAAGG 2366 CCUUAAGGUACCUCAACAG2367 UGUUGAGGUACCUUAAGGG 2368 CCCUUAAGGUACCUCAACA 2369UAAGGGAAGGUCAAGAGGG 2370 CCCUCUUGACCUUCCCUUA 2371 AAGGGAAGGUCAAGAGGGA2372 UCCCUCUUGACCUUCCCUU 2373 CGCUGAGGGAGGAUGCUUA 2374UAAGCAUCCUCCCUCAGCG 2375 UGAGGGAGGAUGCUUAGGG 2376 CCCUAAGCAUCCUCCCUCA2377 GGCACUAAGCCUAAGAAGU 2378 ACUUCUUAGGCUUAGUGCC 2379GCACUAAGCCUAAGAAGUU 2380 AACUUCUUAGGCUUAGUGC 2381 CACUAAGCCUAAGAAGUUC2382 GAACUUCUUAGGCUUAGUG 2383 ACUAAGCCUAAGAAGUUCC 2384GGAACUUCUUAGGCUUAGU 2385 AGAUCGAGUCUCGCUCUGU 2386 ACAGAGCGAGACUCGAUCU2387 GAUCGAGUCUCGCUCUGUC 2388 GACAGAGCGAGACUCGAUC 2389AUCGAGUCUCGCUCUGUCA 2390 UGACAGAGCGAGACUCGAU 2391 AGUCUCGCUCUGUCACCAG2392 CUGGUGACAGAGCGAGACU 2393 GUCUCGCUCUGUCACCAGG 2394CCUGGUGACAGAGCGAGAC 2395 UCUCGCUCUGUCACCAGGC 2396 GCCUGGUGACAGAGCGAGA2397 CUCGCUCUGUCACCAGGCU 2398 AGCCUGGUGACAGAGCGAG 2399GUCACCAGGCUGGAGUGCA 2400 UGCACUCCAGCCUGGUGAC 2401 GGCUCACUGCAACCUCCGU2402 ACGGAGGUUGCAGUGAGCC 2403 GCUCACUGCAACCUCCGUC 2404GACGGAGGUUGCAGUGAGC 2405 UCCGUCUCCUGGGUUCAAG 2406 CUUGAACCCAGGAGACGGA2407 CCGUCUCCUGGGUUCAAGU 2408 ACUUGAACCCAGGAGACGG 2409CGUCUCCUGGGUUCAAGUG 2410 CACUUGAACCCAGGAGACG 2411 GUCUCCUGGGUUCAAGUGA2412 UCACUUGAACCCAGGAGAC 2413 UGGGUUCAAGUGAUUCUUC 2414GAAGAAUCACUUGAACCCA 2415 GGGUUCAAGUGAUUCUUCU 2416 AGAAGAAUCACUUGAACCC2417 GGUUCAAGUGAUUCUUCUG 2418 CAGAAGAAUCACUUGAACC 2419GUUCAAGUGAUUCUUCUGC 2420 GCAGAAGAAUCACUUGAAC 2421 UUCAAGUGAUUCUUCUGCC2422 GGCAGAAGAAUCACUUGAA 2423 UCAAGUGAUUCUUCUGCCU 2424AGGCAGAAGAAUCACUUGA 2425 CGAGCAGCUGGGAUUACAG 2426 CUGUAAUCCCAGCUGCUCG2427 CAGCUGGGAUUACAGGCGC 2428 GCGCCUGUAAUCCCAGCUG 2429ACAUGUUGGCCAGGAUGGU 2430 ACCAUCCUGGCCAACAUGU 2431 CAUGUUGGCCAGGAUGGUC2432 GACCAUCCUGGCCAACAUG 2433 AUGUUGGCCAGGAUGGUCU 2434AGACCAUCCUGGCCAACAU 2435 UGUUGGCCAGGAUGGUCUC 2436 GAGACCAUCCUGGCCAACA2437 GUUGGCCAGGAUGGUCUCA 2438 UGAGACCAUCCUGGCCAAC 2439UUGGCCAGGAUGGUCUCAA 2440 UUGAGACCAUCCUGGCCAA 2441 UGGCCAGGAUGGUCUCAAU2442 AUUGAGACCAUCCUGGCCA 2443 GGCCAGGAUGGUCUCAAUC 2444GAUUGAGACCAUCCUGGCC 2445 GCCAGGAUGGUCUCAAUCU 2446 AGAUUGAGACCAUCCUGGC2447 CCAGGAUGGUCUCAAUCUC 2448 GAGAUUGAGACCAUCCUGG 2449CAGGAUGGUCUCAAUCUCU 2450 AGAGAUUGAGACCAUCCUG 2451 AGGAUGGUCUCAAUCUCUU2452 AAGAGAUUGAGACCAUCCU 2453 AUUAUAGGCGUGAGCCACC 2454GGUGGCUCACGCCUAUAAU 2455 UUAUAGGCGUGAGCCACCG 2456 CGGUGGCUCACGCCUAUAA2457 UAUAGGCGUGAGCCACCGC 2458 GCGGUGGCUCACGCCUAUA 2459GCGCCUGGCUUAUACUUUC 2460 GAAAGUAUAAGCCAGGCGC 2461 CGCCUGGCUUAUACUUUCU2462 AGAAAGUAUAAGCCAGGCG 2463 CCUGGCUUAUACUUUCUUA 2464UAAGAAAGUAUAAGCCAGG 2465 CUGGCUUAUACUUUCUUAA 2466 UUAAGAAAGUAUAAGCCAG2467 CAAAUGUGAGUCAUAAAGA 2468 UCUUUAUGACUCACAUUUG 2469AAUGUGAGUCAUAAAGAAG 2470 CUUCUUUAUGACUCACAUU 2471 UGAGUCAUAAAGAAGGGUU2472 AACCCUUCUUUAUGACUCA 2473 AGUCAUAAAGAAGGGUUAG 2474CUAACCCUUCUUUAUGACU 2475 GUCAUAAAGAAGGGUUAGG 2476 CCUAACCCUUCUUUAUGAC2477 UCAUAAAGAAGGGUUAGGG 2478 CCCUAACCCUUCUUUAUGA 2479CAUAAAGAAGGGUUAGGGU 2480 ACCCUAACCCUUCUUUAUG 2481 AAGAAGGGUUAGGGUGAUG2482 CAUCACCCUAACCCUUCUU 2483 AGAAGGGUUAGGGUGAUGG 2484CCAUCACCCUAACCCUUCU 2485 GAAGGGUUAGGGUGAUGGU 2486 ACCAUCACCCUAACCCUUC2487 AAGGGUUAGGGUGAUGGUC 2488 GACCAUCACCCUAACCCUU 2489AGGGUUAGGGUGAUGGUCC 2490 GGACCAUCACCCUAACCCU 2491 GGGUUAGGGUGAUGGUCCA2492 UGGACCAUCACCCUAACCC 2493 GGGUGAUGGUCCAGAGCAA 2494UUGCUCUGGACCAUCACCC 2495 GGUGAUGGUCCAGAGCAAC 2496 GUUGCUCUGGACCAUCACC2497 ACAGUUCUUCAAGUGUACU 2498 AGUACACUUGAAGAACUGU 2499CAGUUCUUCAAGUGUACUC 2500 GAGUACACUUGAAGAACUG 2501 AGUUCUUCAAGUGUACUCU2502 AGAGUACACUUGAAGAACU 2503 CAAGUGUACUCUGUAGGCU 2504AGCCUACAGAGUACACUUG 2505 AAGUGUACUCUGUAGGCUU 2506 AAGCCUACAGAGUACACUU2507 GUGUACUCUGUAGGCUUCU 2508 AGAAGCCUACAGAGUACAC 2509UGUACUCUGUAGGCUUCUG 2510 CAGAAGCCUACAGAGUACA 2511 GUACUCUGUAGGCUUCUGG2512 CCAGAAGCCUACAGAGUAC 2513 UACUCUGUAGGCUUCUGGG 2514CCCAGAAGCCUACAGAGUA 2515 GUAGGCUUCUGGGAGGUCC 2516 GGACCUCCCAGAAGCCUAC2517 UAGGCUUCUGGGAGGUCCC 2518 GGGACCUCCCAGAAGCCUA 2519AGGCUUCUGGGAGGUCCCU 2520 AGGGACCUCCCAGAAGCCU 2521 GGCUUCUGGGAGGUCCCUU2522 AAGGGACCUCCCAGAAGCC 2523 GCUUCUGGGAGGUCCCUUU 2524AAAGGGACCUCCCAGAAGC 2525 CUUCUGGGAGGUCCCUUUU 2526 AAAAGGGACCUCCCAGAAG2527 UUCUGGGAGGUCCCUUUUC 2528 GAAAAGGGACCUCCCAGAA 2529UCUGGGAGGUCCCUUUUCA 2530 UGAAAAGGGACCUCCCAGA 2531 CAUGUUAUUUGCCUUUUGA2532 UCAAAAGGCAAAUAACAUG 2533 AUUUGCCUUUUGAAUUCUC 2534GAGAAUUCAAAAGGCAAAU 2535 UUUGCCUUUUGAAUUCUCA 2536 UGAGAAUUCAAAAGGCAAA2537 UUGCCUUUUGAAUUCUCAU 2538 AUGAGAAUUCAAAAGGCAA 2539UGCCUUUUGAAUUCUCAUU 2540 AAUGAGAAUUCAAAAGGCA 2541 GCCUUUUGAAUUCUCAUUA2542 UAAUGAGAAUUCAAAAGGC 2543 AUUGUAUUGUGGAGUUUUC 2544GAAAACUCCACAAUACAAU 2545 UUGUAUUGUGGAGUUUUCC 2546 GGAAAACUCCACAAUACAA2547 AGUUUUCCAGAGGCCGUGU 2548 ACACGGCCUCUGGAAAACU 2549GUUUUCCAGAGGCCGUGUG 2550 CACACGGCCUCUGGAAAAC 2551 UUUUCCAGAGGCCGUGUGA2552 UCACACGGCCUCUGGAAAA 2553 UUUCCAGAGGCCGUGUGAC 2554GUCACACGGCCUCUGGAAA 2555 UUCCAGAGGCCGUGUGACA 2556 UGUCACACGGCCUCUGGAA2557 UCCAGAGGCCGUGUGACAU 2558 AUGUCACACGGCCUCUGGA 2559CCAGAGGCCGUGUGACAUG 2560 CAUGUCACACGGCCUCUGG 2561 CAGAGGCCGUGUGACAUGU2562 ACAUGUCACACGGCCUCUG 2563 AGAGGCCGUGUGACAUGUG 2564CACAUGUCACACGGCCUCU 2565 GCCGUGUGACAUGUGAUUA 2566 UAAUCACAUGUCACACGGC2567 CCGUGUGACAUGUGAUUAC 2568 GUAAUCACAUGUCACACGG 2569CGUGUGACAUGUGAUUACA 2570 UGUAAUCACAUGUCACACG 2571 GAUUACAUCAUCUUUCUGA2572 UCAGAAAGAUGAUGUAAUC 2573 AUUACAUCAUCUUUCUGAC 2574GUCAGAAAGAUGAUGUAAU 2575 UUACAUCAUCUUUCUGACA 2576 UGUCAGAAAGAUGAUGUAA2577 UACAUCAUCUUUCUGACAU 2578 AUGUCAGAAAGAUGAUGUA 2579AUCUUUCUGACAUCAUUGU 2580 ACAAUGAUGUCAGAAAGAU 2581 AUUGUUAAUGGAAUGUGUG2582 CACACAUUCCAUUAACAAU 2583

In some embodiments, the siRNA molecules comprise or consist of thenucleotide sequences (sense and antisense strands) shown in Table 4.

TABLE 4 SEQ SEQ ID ID Sense Sequence NO: Antisense Sequence NO:AAAGUGACUAAGAUGCUAA 2584 UUAGCAUCUUAGUCACUUU 2585 AAGUGACUAAGAUGCUAAG2586 CUUAGCAUCUUAGUCACUU 2587 AGUGACUAAGAUGCUAAGA 2588UCUUAGCAUCUUAGUCACU 2589 GUGACUAAGAUGCUAAGAG 2590 CUCUUAGCAUCUUAGUCAC2591 UGACUAAGAUGCUAAGAGC 2592 GCUCUUAGCAUCUUAGUCA 2593GACUAAGAUGCUAAGAGCG 2594 CGCUCUUAGCAUCUUAGUC 2595 ACUAAGAUGCUAAGAGCGU2596 ACGCUCUUAGCAUCUUAGU 2597 CUAAGAUGCUAAGAGCGUA 2598UACGCUCUUAGCAUCUUAG 2599 UAAGAUGCUAAGAGCGUAU 2600 AUACGCUCUUAGCAUCUUA2601 AAGAUGCUAAGAGCGUAUU 2602 AAUACGCUCUUAGCAUCUU 2603AGAUGCUAAGAGCGUAUUU 2604 AAAUACGCUCUUAGCAUCU 2605 GAUGCUAAGAGCGUAUUUA2606 UAAAUACGCUCUUAGCAUC 2607 AUGCUAAGAGCGUAUUUAU 2608AUAAAUACGCUCUUAGCAU 2609 UAAGAGCGUAUUUAUAGCU 2610 AGCUAUAAAUACGCUCUUA2611 AGAGCGUAUUUAUAGCUGA 2612 UCAGCUAUAAAUACGCUCU 2613GAGCGUAUUUAUAGCUGAG 2614 CUCAGCUAUAAAUACGCUC 2615 AGCGUAUUUAUAGCUGAGC2616 GCUCAGCUAUAAAUACGCU 2617 GCGUAUUUAUAGCUGAGCU 2618AGCUCAGCUAUAAAUACGC 2619 CGUAUUUAUAGCUGAGCUC 2620 GAGCUCAGCUAUAAAUACG2621 GUAUUUAUAGCUGAGCUCU 2622 AGAGCUCAGCUAUAAAUAC 2623UAUUUAUAGCUGAGCUCUG 2624 CAGAGCUCAGCUAUAAAUA 2625 AUUUAUAGCUGAGCUCUGA2626 UCAGAGCUCAGCUAUAAAU 2627 UUUAUAGCUGAGCUCUGAC 2628GUCAGAGCUCAGCUAUAAA 2629 UUAUAGCUGAGCUCUGACG 2630 CGUCAGAGCUCAGCUAUAA2631 AGCUGAGCUCUGACGUAAG 2632 CUUACGUCAGAGCUCAGCU 2633GCUGAGCUCUGACGUAAGU 2634 ACUUACGUCAGAGCUCAGC 2635 CUGAGCUCUGACGUAAGUG2636 CACUUACGUCAGAGCUCAG 2637 UGAGCUCUGACGUAAGUGU 2638ACACUUACGUCAGAGCUCA 2639 GAGCUCUGACGUAAGUGUC 2640 GACACUUACGUCAGAGCUC2641 AGGCCAGGCACAGCAGCAA 2642 UUGCUGCUGUGCCUGGCCU 2643CAGCAAGCGGGUGGGAAGA 2644 UCUUCCCACCCGCUUGCUG 2645 AGCAAGCGGGUGGGAAGAG2646 CUCUUCCCACCCGCUUGCU 2647 CAAGCGGGUGGGAAGAGCU 2648AGCUCUUCCCACCCGCUUG 2649 GGGCAUCUGACAGUGAGGG 2650 CCCUCACUGUCAGAUGCCC2651 GGCAUCUGACAGUGAGGGU 2652 ACCCUCACUGUCAGAUGCC 2653GUGACUCCUGCAGCCACUU 2654 AAGUGGCUGCAGGAGUCAC 2655 UGACUCCUGCAGCCACUUC2656 GAAGUGGCUGCAGGAGUCA 2657 ACUCCUGCAGCCACUUCUU 2658AAGAAGUGGCUGCAGGAGU 2659 CUCCUGCAGCCACUUCUUG 2660 CAAGAAGUGGCUGCAGGAG2661 UCCUGCAGCCACUUCUUGU 2662 ACAAGAAGUGGCUGCAGGA 2663CCUGCAGCCACUUCUUGUC 2664 GACAAGAAGUGGCUGCAGG 2665 CUGCAGCCACUUCUUGUCA2666 UGACAAGAAGUGGCUGCAG 2667 UGACUGCCUACUGAUACCA 2668UGGUAUCAGUAGGCAGUCA 2669 GACUGCCUACUGAUACCAA 2670 UUGGUAUCAGUAGGCAGUC2671 ACAGGUAAGCCGUCUGAGG 2672 CCUCAGACGGCUUACCUGU 2673CAGGUAAGCCGUCUGAGGC 2674 GCCUCAGACGGCUUACCUG 2675 AGGUAAGCCGUCUGAGGCA2676 UGCCUCAGACGGCUUACCU 2677 GGUAAGCCGUCUGAGGCAC 2678GUGCCUCAGACGGCUUACC 2679 GUAAGCCGUCUGAGGCACC 2680 GGUGCCUCAGACGGCUUAC2681 UAAGCCGUCUGAGGCACCA 2682 UGGUGCCUCAGACGGCUUA 2683AAGCCGUCUGAGGCACCAC 2684 GUGGUGCCUCAGACGGCUU 2685 UAGAUACCUCCACUUUGCU2686 AGCAAAGUGGAGGUAUCUA 2687 GAUACCUCCACUUUGCUGA 2688UCAGCAAAGUGGAGGUAUC 2689 AUACCUCCACUUUGCUGAC 2690 GUCAGCAAAGUGGAGGUAU2691 CCACUUUGCUGACCAAUGU 2692 ACAUUGGUCAGCAAAGUGG 2693UUUGCUGACCAAUGUUCCA 2694 UGGAACAUUGGUCAGCAAA 2695 UUGCUGACCAAUGUUCCAG2696 CUGGAACAUUGGUCAGCAA 2697 UGCUGACCAAUGUUCCAGA 2698UCUGGAACAUUGGUCAGCA 2699 GCUGACCAAUGUUCCAGAC 2700 GUCUGGAACAUUGGUCAGC2701 CUGACCAAUGUUCCAGACC 2702 GGUCUGGAACAUUGGUCAG 2703CCAAUGUUCCAGACCCGAG 2704 CUCGGGUCUGGAACAUUGG 2705 GGUAGAGGGCUGUCAUUUC2706 GAAAUGACAGCCCUCUACC 2707 GUAGAGGGCUGUCAUUUCC 2708GGAAAUGACAGCCCUCUAC 2709 UGUCAUUUCCCAGCCCAAC 2710 GUUGGGCUGGGAAAUGACA2711 GAAUGGUUGCUGGGAGCUG 2712 CAGCUCCCAGCAACCAUUC 2713CUGGACAGAGCUCUUGAAU 2714 AUUCAAGAGCUCUGUCCAG 2715 UGGACAGAGCUCUUGAAUG2716 CAUUCAAGAGCUCUGUCCA 2717 CAGAGCUCUUGAAUGUGUU 2718AACACAUUCAAGAGCUCUG 2719 AGAGCUCUUGAAUGUGUUU 2720 AAACACAUUCAAGAGCUCU2721 AUGUGUUUCAGAGCUUGGG 2722 CCCAAGCUCUGAAACACAU 2723AAAUGCAGGGUGGACAGGA 2724 UCCUGUCCACCCUGCAUUU 2725 AAUGCAGGGUGGACAGGAG2726 CUCCUGUCCACCCUGCAUU 2727 AUGCAGGGUGGACAGGAGG 2728CCUCCUGUCCACCCUGCAU 2729 GGUGGACAGGAGGGUCUAA 2730 UUAGACCCUCCUGUCCACC2731 GUGGACAGGAGGGUCUAAU 2732 AUUAGACCCUCCUGUCCAC 2733UGGACAGGAGGGUCUAAUC 2734 GAUUAGACCCUCCUGUCCA 2735 GGACAGGAGGGUCUAAUCG2736 CGAUUAGACCCUCCUGUCC 2737 GACAGGAGGGUCUAAUCGU 2738ACGAUUAGACCCUCCUGUC 2739 ACAGGAGGGUCUAAUCGUC 2740 GACGAUUAGACCCUCCUGU2741 CAGGAGGGUCUAAUCGUCU 2742 AGACGAUUAGACCCUCCUG 2743AGGAGGGUCUAAUCGUCUC 2744 GAGACGAUUAGACCCUCCU 2745 GGAGGGUCUAAUCGUCUCA2746 UGAGACGAUUAGACCCUCC 2747 GAGGGUCUAAUCGUCUCAG 2748CUGAGACGAUUAGACCCUC 2749 AGGGUCUAAUCGUCUCAGU 2750 ACUGAGACGAUUAGACCCU2751 GGGUCUAAUCGUCUCAGUG 2752 CACUGAGACGAUUAGACCC 2743GGUCUAAUCGUCUCAGUGC 2754 GCACUGAGACGAUUAGACC 2755 CCCACCAAAGAGUGCCCUG2756 CAGGGCACUCUUUGGUGGG 2757 CCACCAAAGAGUGCCCUGA 2758UCAGGGCACUCUUUGGUGG 2759 CCAAAGAGUGCCCUGAGGU 2760 ACCUCAGGGCACUCUUUGG2761 CAAAGAGUGCCCUGAGGUU 2762 AACCUCAGGGCACUCUUUG 2763AAAGAGUGCCCUGAGGUUC 2764 GAACCUCAGGGCACUCUUU 2765 AAGAGUGCCCUGAGGUUCU2766 AGAACCUCAGGGCACUCUU 2767 AGAGUGCCCUGAGGUUCUA 2768UAGAACCUCAGGGCACUCU 2769 GAGUGCCCUGAGGUUCUAG 2770 CUAGAACCUCAGGGCACUC2771 AGUGCCCUGAGGUUCUAGG 2772 CCUAGAACCUCAGGGCACU 2773GUGCCCUGAGGUUCUAGGA 2774 UCCUAGAACCUCAGGGCAC 2775 CCUGAGGUUCUAGGAAGAG2776 CUCUUCCUAGAACCUCAGG 2777 CUGAGGUUCUAGGAAGAGC 2778GCUCUUCCUAGAACCUCAG 2779 UUCUAGGAAGAGCCUGGUA 2780 UACCAGGCUCUUCCUAGAA2781 UCUAGGAAGAGCCUGGUAC 2782 GUACCAGGCUCUUCCUAGA 2783CUAGGAAGAGCCUGGUACA 2784 UGUACCAGGCUCUUCCUAG 2785 UAGGAAGAGCCUGGUACAU2786 AUGUACCAGGCUCUUCCUA 2787 AGGAAGAGCCUGGUACAUC 2788GAUGUACCAGGCUCUUCCU 2789 GGAAGAGCCUGGUACAUCA 2790 UGAUGUACCAGGCUCUUCC2791 GAAGAGCCUGGUACAUCAC 2792 GUGAUGUACCAGGCUCUUC 2793AAGAGCCUGGUACAUCACC 2794 GGUGAUGUACCAGGCUCUU 2795 UCACCAAGCUCCAUUGCCA2796 UGGCAAUGGAGCUUGGUGA 2797 CACCAAGCUCCAUUGCCAC 2798GUGGCAAUGGAGCUUGGUG 2799 ACCAAGCUCCAUUGCCACG 2800 CGUGGCAAUGGAGCUUGGU2801 CCAAGCUCCAUUGCCACGU 2802 ACGUGGCAAUGGAGCUUGG 2803CAAGCUCCAUUGCCACGUG 2804 CACGUGGCAAUGGAGCUUG 2805 AAGCUCCAUUGCCACGUGU2806 ACACGUGGCAAUGGAGCUU 2807 AGCUCCAUUGCCACGUGUU 2808AACACGUGGCAAUGGAGCU 2809 CUCCAUUGCCACGUGUUUG 2810 CAAACACGUGGCAAUGGAG2811 UCCAUUGCCACGUGUUUGU 2812 ACAAACACGUGGCAAUGGA 2813CCAUUGCCACGUGUUUGUG 2814 CACAAACACGUGGCAAUGG 2815 CAUUGCCACGUGUUUGUGU2816 ACACAAACACGUGGCAAUG 2817 AAAGGUAGCAGUGAUGUGG 2818CCACAUCACUGCUACCUUU 2819 AAGGUAGCAGUGAUGUGGA 2820 UCCACAUCACUGCUACCUU2821 AGGUAGCAGUGAUGUGGAU 2822 AUCCACAUCACUGCUACCU 2823GGUAGCAGUGAUGUGGAUC 2824 GAUCCACAUCACUGCUACC 2825 GUAGCAGUGAUGUGGAUCC2826 GGAUCCACAUCACUGCUAC 2827 UAGCAGUGAUGUGGAUCCU 2828AGGAUCCACAUCACUGCUA 2829 AGCAGUGAUGUGGAUCCUG 2830 CAGGAUCCACAUCACUGCU2831 GCAGUGAUGUGGAUCCUGA 2832 UCAGGAUCCACAUCACUGC 2833CAGUGAUGUGGAUCCUGAA 2834 UUCAGGAUCCACAUCACUG 2835 AGUGAUGUGGAUCCUGAAG2836 CUUCAGGAUCCACAUCACU 2837 GUGAUGUGGAUCCUGAAGA 2838UCUUCAGGAUCCACAUCAC 2839 GAUGUGGAUCCUGAAGACA 2840 UGUCUUCAGGAUCCACAUC2841 AUGUGGAUCCUGAAGACAG 2842 CUGUCUUCAGGAUCCACAU 2843UGUGGAUCCUGAAGACAGU 2844 ACUGUCUUCAGGAUCCACA 2845 GUGGAUCCUGAAGACAGUC2846 GACUGUCUUCAGGAUCCAC 2847 AUCCUGAAGACAGUCUCUC 2848GAGAGACUGUCUUCAGGAU 2849 UCCUGAAGACAGUCUCUCU 2850 AGAGAGACUGUCUUCAGGA2851 AGACAGUCUCUCUUCUCUG 2852 CAGAGAAGAGAGACUGUCU 2853AGUCUCUCUUCUCUGGCAG 2854 CUGCCAGAGAAGAGAGACU 2855 CUCUUCUCUGGCAGUGUGA2856 UCACACUGCCAGAGAAGAG 2857 AACCAGCUUGUCCCUGUCU 2858AGACAGGGACAAGCUGGUU 2859 CAGCUUGUCCCUGUCUCUU 2860 AAGAGACAGGGACAAGCUG2861 CAGCUGCUGUCCAGAGGCA 2862 UGCCUCUGGACAGCAGCUG 2863CACGGCACUGCCACAUGGU 2864 ACCAUGUGGCAGUGCCGUG 2865 ACGGCACUGCCACAUGGUG2866 CACCAUGUGGCAGUGCCGU 2867 AUGGUGGACACUGGUGGUA 2868UACCACCAGUGUCCACCAU 2869 UGGUGGACACUGGUGGUAC 2870 GUACCACCAGUGUCCACCA2871 GGUGGACACUGGUGGUACU 2872 AGUACCACCAGUGUCCACC 2873GUGGACACUGGUGGUACUG 2874 CAGUACCACCAGUGUCCAC 2875 UGGACACUGGUGGUACUGA2876 UCAGUACCACCAGUGUCCA 2877 GGACACUGGUGGUACUGAG 2878CUCAGUACCACCAGUGUCC 2879 GACACUGGUGGUACUGAGG 2880 CCUCAGUACCACCAGUGUC2881 ACACUGGUGGUACUGAGGU 2882 ACCUCAGUACCACCAGUGU 2883CACUGGUGGUACUGAGGUC 2884 GACCUCAGUACCACCAGUG 2885 ACUGGUGGUACUGAGGUCC2886 GGACCUCAGUACCACCAGU 2887 CUGGUGGUACUGAGGUCCA 2888UGGACCUCAGUACCACCAG 2889 UACUGAGGUCCAGCCUUCC 2890 GGAAGGCUGGACCUCAGUA2891 CUGAGGUCCAGCCUUCCAA 2892 UUGGAAGGCUGGACCUCAG 2893UGAGGUCCAGCCUUCCAAU 2894 AUUGGAAGGCUGGACCUCA 2895 GAGGUCCAGCCUUCCAAUU2896 AAUUGGAAGGCUGGACCUC 2897 AGGUCCAGCCUUCCAAUUA 2898UAAUUGGAAGGCUGGACCU 2899 GGUCCAGCCUUCCAAUUAG 2900 CUAAUUGGAAGGCUGGACC2901 GUCCAGCCUUCCAAUUAGG 2902 CCUAAUUGGAAGGCUGGAC 2903UCCAGCCUUCCAAUUAGGA 2904 UCCUAAUUGGAAGGCUGGA 2905 GCCUAGAUCUAAUAGUCUC2906 GAGACUAUUAGAUCUAGGC 2907 CCUAGAUCUAAUAGUCUCU 2908AGAGACUAUUAGAUCUAGG 2909 CUAGAUCUAAUAGUCUCUC 2910 GAGAGACUAUUAGAUCUAG2911 UAGAUCUAAUAGUCUCUCU 2912 AGAGAGACUAUUAGAUCUA 2913CUAAUAGUCUCUCUUGACA 2914 UGUCAAGAGAGACUAUUAG 2915 UAAUAGUCUCUCUUGACAG2916 CUGUCAAGAGAGACUAUUA 2917 AAUAGUCUCUCUUGACAGC 2918GCUGUCAAGAGAGACUAUU 2919 AUGAGCAAAGUGGAGUAAA 2920 UUUACUCCACUUUGCUCAU2921 UGAGCAAAGUGGAGUAAAG 2922 CUUUACUCCACUUUGCUCA 2923GAGCAAAGUGGAGUAAAGA 2924 UCUUUACUCCACUUUGCUC 2925 GCAAAGUGGAGUAAAGACA2926 UGUCUUUACUCCACUUUGC 2927 CAAAGUGGAGUAAAGACAC 2928GUGUCUUUACUCCACUUUG 2929 AUUUCCAAAUCACACCCAC 2930 GUGGGUGUGAUUUGGAAAU2931 UCCAAAUCACACCCACUUC 2932 GAAGUGGGUGUGAUUUGGA 2933CCAAAUCACACCCACUUCC 2934 GGAAGUGGGUGUGAUUUGG 2935 AAAAGCUAGCAUGAGGCCC2936 GGGCCUCAUGCUAGCUUUU 2937 AAAGCUAGCAUGAGGCCCA 2938UGGGCCUCAUGCUAGCUUU 2939 AAGCUAGCAUGAGGCCCAC 2940 GUGGGCCUCAUGCUAGCUU2941 CCCACCUUCAUGAAUUCAA 2942 UUGAAUUCAUGAAGGUGGG 2943ACCUUCAUGAAUUCAAUGU 2944 ACAUUGAAUUCAUGAAGGU 2945 CCUUCAUGAAUUCAAUGUG2946 CACAUUGAAUUCAUGAAGG 2947 CUUCAUGAAUUCAAUGUGG 2948CCACAUUGAAUUCAUGAAG 2949 UCAUGAAUUCAAUGUGGAG 2950 CUCCACAUUGAAUUCAUGA2951 CAUGAAUUCAAUGUGGAGG 2952 CCUCCACAUUGAAUUCAUG 2953CAUUUAAAGCCAGUGAGGA 2954 UCCUCACUGGCUUUAAAUG 2955 UUUAAAGCCAGUGAGGACU2956 AGUCCUCACUGGCUUUAAA 2957 AGGACUGGGUGUGGUGGCU 2958AGCCACCACACCCAGUCCU 2959 GACUGGGUGUGGUGGCUCA 2960 UGAGCCACCACACCCAGUC2961 ACUGGGUGUGGUGGCUCAU 2962 AUGAGCCACCACACCCAGU 2963CUGGGUGUGGUGGCUCAUG 2964 CAUGAGCCACCACACCCAG 2965 UGGGUGUGGUGGCUCAUGU2966 ACAUGAGCCACCACACCCA 2967 GGGUGUGGUGGCUCAUGUC 2968GACAUGAGCCACCACACCC 2969 GGUGUGGUGGCUCAUGUCU 2970 AGACAUGAGCCACCACACC2971 GUGUGGUGGCUCAUGUCUA 2972 UAGACAUGAGCCACCACAC 2973UGUGGUGGCUCAUGUCUAU 2974 AUAGACAUGAGCCACCACA 2975 GAGGAUCGCUUGAGCCCAG2976 CUGGGCUCAAGCGAUCCUC 2977 AAAUAAAUUAGCCUGUGUG 2978CACACAGGCUAAUUUAUUU 2979 AAUUAGCCUGUGUGGUGUG 2980 CACACCACACAGGCUAAUU2981 AUUAGCCUGUGUGGUGUGG 2982 CCACACCACACAGGCUAAU 2983GCCUGUGUGGUGUGGUGUG 2984 CACACCACACCACACAGGC 2985 UGUGGUGUGGUGUGGUUGG2986 CCAACCACACCACACCACA 2987 GGUGUGGUGUGGUUGGUGU 2988ACACCAACCACACCACACC 2989 UGUGGUUGGUGUGGUGGCA 2990 UGCCACCACACCAACCACA2991 GUGGUUGGUGUGGUGGCAC 2992 GUGCCACCACACCAACCAC 2993UGGUUGGUGUGGUGGCACG 2994 CGUGCCACCACACCAACCA 2995 CACGCACCUGUAGACUUAG2996 CUAAGUCUACAGGUGCGUG 2997 ACGCACCUGUAGACUUAGC 2998GCUAAGUCUACAGGUGCGU 2999 AGACUUAGCUACUCUGGAA 3000 UUCCAGAGUAGCUAAGUCU3001 GACUUAGCUACUCUGGAAG 3002 CUUCCAGAGUAGCUAAGUC 3003ACUUAGCUACUCUGGAAGC 3004 GCUUCCAGAGUAGCUAAGU 3005 GGAAGAAUCACUUAACCCA3006 UGGGUUAAGUGAUUCUUCC 3007 UCACUUAACCCAGGAGGUC 3008GACCUCCUGGGUUAAGUGA 3009 UUAACCCAGGAGGUCAAGG 3010 CCUUGACCUCCUGGGUUAA3011 UAACCCAGGAGGUCAAGGC 3012 GCCUUGACCUCCUGGGUUA 3013GUCAAGGCUGCAGUGAGCU 3014 AGCUCACUGCAGCCUUGAC 3015 UCAAGGCUGCAGUGAGCUG3016 CAGCUCACUGCAGCCUUGA 3017 CAAGGCUGCAGUGAGCUGU 3018ACAGCUCACUGCAGCCUUG 3019 AAGGCUGCAGUGAGCUGUG 3020 CACAGCUCACUGCAGCCUU3021 CUGCAGUGAGCUGUGAUCA 3022 UGAUCACAGCUCACUGCAG 3023GUCAGGUGCGGUGGCUCAU 3024 AUGAGCCACCGCACCUGAC 3025 UCAGGUGCGGUGGCUCAUG3026 CAUGAGCCACCGCACCUGA 3027 UGCGGUGGCUCAUGCCUGU 3028ACAGGCAUGAGCCACCGCA 3029 GCGGUGGCUCAUGCCUGUA 3030 UACAGGCAUGAGCCACCGC3031 CGGUGGCUCAUGCCUGUAA 3032 UUACAGGCAUGAGCCACCG 3033GGUGGCUCAUGCCUGUAAU 3034 AUUACAGGCAUGAGCCACC 3035 GUGGCUCAUGCCUGUAAUC3036 GAUUACAGGCAUGAGCCAC 3037 UGGCUCAUGCCUGUAAUCC 3038GGAUUACAGGCAUGAGCCA 3039 GGCUCAUGCCUGUAAUCCC 3040 GGGAUUACAGGCAUGAGCC3041 AUGCCUGUAAUCCCAGCAC 3042 GUGCUGGGAUUACAGGCAU 3043CAGCACUUUGGGAGGCCGA 3044 UCGGCCUCCCAAAGUGCUG 3045 AGCACUUUGGGAGGCCGAG3046 CUCGGCCUCCCAAAGUGCU 3047 GCACCUGUAGUCCCAGCGA 3048UCGCUGGGACUACAGGUGC 3049 CACCUGUAGUCCCAGCGAC 3050 GUCGCUGGGACUACAGGUG3051 GGAGGCUGAGGCAGAAGAA 3052 UUCUUCUGCCUCAGCCUCC 3053GAGGCUGAGGCAGAAGAAU 3054 AUUCUUCUGCCUCAGCCUC 3055 AGGCUGAGGCAGAAGAAUG3056 CAUUCUUCUGCCUCAGCCU 3057 GGCUGAGGCAGAAGAAUGG 3058CCAUUCUUCUGCCUCAGCC 3059 GCUGAGGCAGAAGAAUGGU 3060 ACCAUUCUUCUGCCUCAGC3061 CUGAGGCAGAAGAAUGGUG 3062 CACCAUUCUUCUGCCUCAG 3063UGAGGCAGAAGAAUGGUGU 3064 ACACCAUUCUUCUGCCUCA 3065 GAGCUUGCAGUGAGCCGAG3066 CUCGGCUCACUGCAAGCUC 3067 AAAAUGUGGUCAGGAGGGC 3068GCCCUCCUGACCACAUUUU 3069 AACCAAGACUGCUGUAUUU 3070 AAAUACAGCAGUCUUGGUU3071 ACCAAGACUGCUGUAUUUG 3072 CAAAUACAGCAGUCUUGGU 3073CCAAGACUGCUGUAUUUGC 3074 GCAAAUACAGCAGUCUUGG 3075 CAAGACUGCUGUAUUUGCC3076 GGCAAAUACAGCAGUCUUG 3077 AAGACUGCUGUAUUUGCCU 3078AGGCAAAUACAGCAGUCUU 3079 GCUGUAUUUGCCUUGCUUU 3080 AAAGCAAGGCAAAUACAGC3081 UUGCCUUGCUUUGUUGUCA 3082 UGACAACAAAGCAAGGCAA 3083UGCCUUGCUUUGUUGUCAA 3084 UUGACAACAAAGCAAGGCA 3085 UUGUUGUCAAAAGCUCUUA3086 UAAGAGCUUUUGACAACAA 3087 UGUUGUCAAAAGCUCUUAG 3088CUAAGAGCUUUUGACAACA 3089 GUUGUCAAAAGCUCUUAGA 3090 UCUAAGAGCUUUUGACAAC3091 UUGUCAAAAGCUCUUAGAG 3092 CUCUAAGAGCUUUUGACAA 3093UCUUAGAGCUCCCAUUUUC 3094 GAAAAUGGGAGCUCUAAGA 3095 ACUUUAGGAGGCUGAGGCA3096 UGCCUCAGCCUCCUAAAGU 3097 CUUUAGGAGGCUGAGGCAA 3098UUGCCUCAGCCUCCUAAAG 3099 UUUAGGAGGCUGAGGCAAG 3100 CUUGCCUCAGCCUCCUAAA3101 UUAGGAGGCUGAGGCAAGU 3102 ACUUGCCUCAGCCUCCUAA 3103UAGGAGGCUGAGGCAAGUG 3104 CACUUGCCUCAGCCUCCUA 3105 AGGAGGCUGAGGCAAGUGG3106 CCACUUGCCUCAGCCUCCU 3107 GGAGGCUGAGGCAAGUGGA 3108UCCACUUGCCUCAGCCUCC 3109 GAGGCUGAGGCAAGUGGAU 3110 AUCCACUUGCCUCAGCCUC3111 GUGGAUUGCUUGAGCCCAG 3112 CUGGGCUCAAGCAAUCCAC 3113UGGAUUGCUUGAGCCCAGG 3114 CCUGGGCUCAAGCAAUCCA 3115 GGAUUGCUUGAGCCCAGGA3116 UCCUGGGCUCAAGCAAUCC 3117 GAUUGCUUGAGCCCAGGAG 3118CUCCUGGGCUCAAGCAAUC 3119 AUUGCUUGAGCCCAGGAGU 3120 ACUCCUGGGCUCAAGCAAU3121 UUGCUUGAGCCCAGGAGUU 3122 AACUCCUGGGCUCAAGCAA 3123UGCUUGAGCCCAGGAGUUC 3124 GAACUCCUGGGCUCAAGCA 3125 UGAGCCCAGGAGUUCAAGA3126 UCUUGAACUCCUGGGCUCA 3127 AUUAGCCAGGUGUGGUGGU 3128ACCACCACACCUGGCUAAU 3129 UUAGCCAGGUGUGGUGGUG 3130 CACCACCACACCUGGCUAA3131 GUGCGCACCUGUAGUCCCA 3132 UGGGACUACAGGUGCGCAC 3133UGCGCACCUGUAGUCCCAA 3134 UUGGGACUACAGGUGCGCA 3135 GCGCACCUGUAGUCCCAAC3136 GUUGGGACUACAGGUGCGC 3137 CGCACCUGUAGUCCCAACU 3138AGUUGGGACUACAGGUGCG 3139 UACUAAGGAGGCUGAGGCA 3140 UGCCUCAGCCUCCUUAGUA3141 ACUAAGGAGGCUGAGGCAG 3142 CUGCCUCAGCCUCCUUAGU 3143UUCAAGGCUGCAGUGAGCU 3144 AGCUCACUGCAGCCUUGAA 3145 UCAAGGCUGCAGUGAGCUA3146 UAGCUCACUGCAGCCUUGA 3147 CAAGGCUGCAGUGAGCUAU 3148AUAGCUCACUGCAGCCUUG 3149 AAGGCUGCAGUGAGCUAUG 3150 CAUAGCUCACUGCAGCCUU3151 UGCAGUGAGCUAUGAUUGU 3152 ACAAUCAUAGCUCACUGCA 3153GCAGUGAGCUAUGAUUGUG 3154 CACAAUCAUAGCUCACUGC 3155 CAGUGAGCUAUGAUUGUGC3156 GCACAAUCAUAGCUCACUG 3157 GGAGGCCUGGCACUACUUC 3158GAAGUAGUGCCAGGCCUCC 3159 GAGGCCUGGCACUACUUCU 3160 AGAAGUAGUGCCAGGCCUC3161 AGGCCUGGCACUACUUCUA 3162 UAGAAGUAGUGCCAGGCCU 3163GGCCUGGCACUACUUCUAG 3164 CUAGAAGUAGUGCCAGGCC 3165 GCCUGGCACUACUUCUAGG3166 CCUAGAAGUAGUGCCAGGC 3167 CCUGGCACUACUUCUAGGA 3168UCCUAGAAGUAGUGCCAGG 3169 CUGGCACUACUUCUAGGAU 3170 AUCCUAGAAGUAGUGCCAG3171 UGGCACUACUUCUAGGAUG 3172 CAUCCUAGAAGUAGUGCCA 3173AAUUUAGGCAACUCUCACA 3174 UGUGAGAGUUGCCUAAAUU 3175 AUUUAGGCAACUCUCACAG3176 CUGUGAGAGUUGCCUAAAU 3177 UUUAGGCAACUCUCACAGU 3178ACUGUGAGAGUUGCCUAAA 3179 UUAGGCAACUCUCACAGUC 3180 GACUGUGAGAGUUGCCUAA3181 UAGGCAACUCUCACAGUCC 3182 GGACUGUGAGAGUUGCCUA 3183AGGCAACUCUCACAGUCCC 3184 GGGACUGUGAGAGUUGCCU 3185 GGCAACUCUCACAGUCCCU3186 AGGGACUGUGAGAGUUGCC 3187 GCAACUCUCACAGUCCCUU 3188AAGGGACUGUGAGAGUUGC 3189 CAACUCUCACAGUCCCUUG 3190 CAAGGGACUGUGAGAGUUG3191 AACUCUCACAGUCCCUUGA 3192 UCAAGGGACUGUGAGAGUU 3193ACUCUCACAGUCCCUUGAA 3194 UUCAAGGGACUGUGAGAGU 3195 AGAAGUGGCAGCUGGGUAU3196 AUACCCAGCUGCCACUUCU 3197 GAAGUGGCAGCUGGGUAUA 3198UAUACCCAGCUGCCACUUC 3199 AAGUGGCAGCUGGGUAUAG 3200 CUAUACCCAGCUGCCACUU3201 AGUGGCAGCUGGGUAUAGG 3202 CCUAUACCCAGCUGCCACU 3203GUGGCAGCUGGGUAUAGGC 3204 GCCUAUACCCAGCUGCCAC 3205 UGGCAGCUGGGUAUAGGCC3206 GGCCUAUACCCAGCUGCCA 3207 GCAGCUGGGUAUAGGCCCU 3208AGGGCCUAUACCCAGCUGC 3209 CAGCUGGGUAUAGGCCCUC 3210 GAGGGCCUAUACCCAGCUG3211 AGCUGGGUAUAGGCCCUCC 3212 GGAGGGCCUAUACCCAGCU 3213GGUAUAGGCCCUCCCAAGU 3214 ACUUGGGAGGGCCUAUACC 3215 GUAUAGGCCCUCCCAAGUG3216 CACUUGGGAGGGCCUAUAC 3217 UAUAGGCCCUCCCAAGUGU 3218ACACUUGGGAGGGCCUAUA 3219 AUAGGCCCUCCCAAGUGUC 3220 GACACUUGGGAGGGCCUAU3221 UAGGCCCUCCCAAGUGUCA 3222 UGACACUUGGGAGGGCCUA 3223CCCUCCCAAGUGUCAUGCC 3224 GGCAUGACACUUGGGAGGG 3225 CCUCCCAAGUGUCAUGCCC3226 GGGCAUGACACUUGGGAGG 3227 CCCUGACAGUCCUGAUGGA 3228UCCAUCAGGACUGUCAGGG 3229 CUGAUGGACUCUGCCCUGU 3230 ACAGGGCAGAGUCCAUCAG3231 UGAUGGACUCUGCCCUGUG 3232 CACAGGGCAGAGUCCAUCA 3233UGGACUCUGCCCUGUGUAA 3234 UUACACAGGGCAGAGUCCA 3235 GGACUCUGCCCUGUGUAAG3236 CUUACACAGGGCAGAGUCC 3237 GACUCUGCCCUGUGUAAGA 3238UCUUACACAGGGCAGAGUC 3239 CUGCCCUGUGUAAGAUUGC 3240 GCAAUCUUACACAGGGCAG3241 UGCCCUGUGUAAGAUUGCA 3242 UGCAAUCUUACACAGGGCA 3243GCCCUGUGUAAGAUUGCAU 3244 AUGCAAUCUUACACAGGGC 3245 CCCUGUGUAAGAUUGCAUC3246 GAUGCAAUCUUACACAGGG 3247 CUGUGUAAGAUUGCAUCAC 3248GUGAUGCAAUCUUACACAG 3249 UGUGUAAGAUUGCAUCACC 3250 GGUGAUGCAAUCUUACACA3251 GUGUAAGAUUGCAUCACCA 3252 UGGUGAUGCAAUCUUACAC 3253UGUAAGAUUGCAUCACCAC 3254 GUGGUGAUGCAAUCUUACA 3255 CACCACCACCACCACCUCU3256 AGAGGUGGUGGUGGUGGUG 3257 ACCACCACCACCACCUCUC 3258GAGAGGUGGUGGUGGUGGU 3259 CCACCACCACCACCUCUCU 3260 AGAGAGGUGGUGGUGGUGG3261 CACCACCACCACCUCUCUG 3262 CAGAGAGGUGGUGGUGGUG 3263ACCACCACCACCUCUCUGG 3264 CCAGAGAGGUGGUGGUGGU 3265 UGGCCCUCCUCCACAUCAU3266 AUGAUGUGGAGGAGGGCCA 3267 GGCCCUCCUCCACAUCAUG 3268CAUGAUGUGGAGGAGGGCC 3269 GCCCUCCUCCACAUCAUGC 3270 GCAUGAUGUGGAGGAGGGC3271 CCCUCCUCCACAUCAUGCU 3272 AGCAUGAUGUGGAGGAGGG 3273CCUCCUCCACAUCAUGCUC 3274 GAGCAUGAUGUGGAGGAGG 3275 CUCCUCCACAUCAUGCUCC3276 GGAGCAUGAUGUGGAGGAG 3277 UCCUCCACAUCAUGCUCCA 3278UGGAGCAUGAUGUGGAGGA 3279 CCUCCACAUCAUGCUCCAC 3280 GUGGAGCAUGAUGUGGAGG3281 CUCCACAUCAUGCUCCACA 3282 UGUGGAGCAUGAUGUGGAG 3283ACAUCAUGCUCCACAUCAU 3284 AUGAUGUGGAGCAUGAUGU 3285 AUGCUCCACAUCAUGCUCC3286 GGAGCAUGAUGUGGAGCAU 3287 GCUCCACAUCAUGCUCCAG 3288CUGGAGCAUGAUGUGGAGC 3289 CUCCACAUCAUGCUCCAGG 3290 CCUGGAGCAUGAUGUGGAG3291 UCCACAUCAUGCUCCAGGC 3292 GCCUGGAGCAUGAUGUGGA 3293CCACAUCAUGCUCCAGGCC 3294 GGCCUGGAGCAUGAUGUGG 3295 CACAUCAUGCUCCAGGCCA3296 UGGCCUGGAGCAUGAUGUG 3297 ACAUCAUGCUCCAGGCCAA 3298UUGGCCUGGAGCAUGAUGU 3299 CAUCAUGCUCCAGGCCAAC 3300 GUUGGCCUGGAGCAUGAUG3301 AUCAUGCUCCAGGCCAACU 3302 AGUUGGCCUGGAGCAUGAU 3303UCAUGCUCCAGGCCAACUG 3304 CAGUUGGCCUGGAGCAUGA 3305 GUGACUUCUGUGCCUCGUG3306 CACGAGGCACAGAAGUCAC 3307 UGACUUCUGUGCCUCGUGG 3308CCACGAGGCACAGAAGUCA 3309 GACUUCUGUGCCUCGUGGC 3310 GCCACGAGGCACAGAAGUC3311 CACCUGGGCCUGAGCAAGA 3312 UCUUGCUCAGGCCCAGGUG 3313ACCUGGGCCUGAGCAAGAG 3314 CUCUUGCUCAGGCCCAGGU 3315 AGCAAGAGGGCUCCAUUCU3316 AGAAUGGAGCCCUCUUGCU 3317 GCAAGAGGGCUCCAUUCUC 3318GAGAAUGGAGCCCUCUUGC 3319 CAAGAGGGCUCCAUUCUCC 3320 GGAGAAUGGAGCCCUCUUG3321 AGAGGGCUCCAUUCUCCUA 3322 UAGGAGAAUGGAGCCCUCU 3323GAGGGCUCCAUUCUCCUAC 3324 GUAGGAGAAUGGAGCCCUC 3325 AGGGCUCCAUUCUCCUACC3326 GGUAGGAGAAUGGAGCCCU 3327 GGGCUCCAUUCUCCUACCC 3328GGGUAGGAGAAUGGAGCCC 3329 AACCCUCAUCCCUGUCCUA 3330 UAGGACAGGGAUGAGGGUU3331 ACCCUCAUCCCUGUCCUAG 3332 CUAGGACAGGGAUGAGGGU 3333CCCUCAUCCCUGUCCUAGC 3334 GCUAGGACAGGGAUGAGGG 3335 CCUCAUCCCUGUCCUAGCC3336 GGCUAGGACAGGGAUGAGG 3337 GAAUUUUCCUUCUGGCCUA 3338UAGGCCAGAAGGAAAAUUC 3339 AAUUUUCCUUCUGGCCUAA 3340 UUAGGCCAGAAGGAAAAUU3341 UGCUGCAGCAGUGGUGAAG 3342 CUUCACCACUGCUGCAGCA 3343GCUGCAGCAGUGGUGAAGC 3344 GCUUCACCACUGCUGCAGC 3345 CUGCAGCAGUGGUGAAGCU3346 AGCUUCACCACUGCUGCAG 3347 UGCAGCAGUGGUGAAGCUA 3348UAGCUUCACCACUGCUGCA 3349 AAAGACUAGAGGUAUGAGG 3350 CCUCAUACCUCUAGUCUUU3351 AAGACUAGAGGUAUGAGGG 3352 CCCUCAUACCUCUAGUCUU 3353AGACUAGAGGUAUGAGGGA 3354 UCCCUCAUACCUCUAGUCU 3355 GACUAGAGGUAUGAGGGAA3356 UUCCCUCAUACCUCUAGUC 3357 CCCACCUGGCUCAUAAGGC 3358GCCUUAUGAGCCAGGUGGG 3359 CCACCUGGCUCAUAAGGCG 3360 CGCCUUAUGAGCCAGGUGG3361 CACCUGGCUCAUAAGGCGU 3362 ACGCCUUAUGAGCCAGGUG 3363ACCUGGCUCAUAAGGCGUU 3364 AACGCCUUAUGAGCCAGGU 3365 CUGGCUCAUAAGGCGUUCC3366 GGAACGCCUUAUGAGCCAG 3367 CUCAUAAGGCGUUCCCUCC 3368GGAGGGAACGCCUUAUGAG 3369 UCAUAAGGCGUUCCCUCCC 3370 GGGAGGGAACGCCUUAUGA3371 AAAUCAUCCUCUUUCUUGC 3372 GCAAGAAAGAGGAUGAUUU 3373AAUCAUCCUCUUUCUUGCA 3374 UGCAAGAAAGAGGAUGAUU 3375 UCAUCCUCUUUCUUGCAUC3376 GAUGCAAGAAAGAGGAUGA 3377 CAUCCUCUUUCUUGCAUCA 3378UGAUGCAAGAAAGAGGAUG 3379 AUCCUCUUUCUUGCAUCAU 3380 AUGAUGCAAGAAAGAGGAU3381 UCCUCUUUCUUGCAUCAUG 3382 CAUGAUGCAAGAAAGAGGA 3383CUCUUUCUUGCAUCAUGCG 3384 CGCAUGAUGCAAGAAAGAG 3385 UCUUUCUUGCAUCAUGCGU3386 ACGCAUGAUGCAAGAAAGA 3387 CUUUCUUGCAUCAUGCGUG 3388CACGCAUGAUGCAAGAAAG 3389 UUUCUUGCAUCAUGCGUGU 3390 ACACGCAUGAUGCAAGAAA3391 UUCUUGCAUCAUGCGUGUC 3392 GACACGCAUGAUGCAAGAA 3393UCUUGCAUCAUGCGUGUCC 3394 GGACACGCAUGAUGCAAGA 3395 CUUGCAUCAUGCGUGUCCA3396 UGGACACGCAUGAUGCAAG 3397 UCAUGCGUGUCCACAUUGC 3398GCAAUGUGGACACGCAUGA 3399 CAUGCGUGUCCACAUUGCA 3400 UGCAAUGUGGACACGCAUG3401 CCCUACUUCAGGCCCAGUC 3402 GACUGGGCCUGAAGUAGGG 3403CCUACUUCAGGCCCAGUCA 3404 UGACUGGGCCUGAAGUAGG 3405 UUCAGGCCCAGUCACCAUG3406 CAUGGUGACUGGGCCUGAA 3407 UCAGGCCCAGUCACCAUGG 3408CCAUGGUGACUGGGCCUGA 3409 CCAGUCACCAUGGCCAGAU 3410 AUCUGGCCAUGGUGACUGG3411 CAGUCACCAUGGCCAGAUG 3412 CAUCUGGCCAUGGUGACUG 3413AGCACAGCUGGCCAAUCCU 3414 AGGAUUGGCCAGCUGUGCU 3415 GCACAGCUGGCCAAUCCUG3416 CAGGAUUGGCCAGCUGUGC 3417 AGCUGGCCAAUCCUGGGAC 3418GUCCCAGGAUUGGCCAGCU 3419 GCUGGCCAAUCCUGGGACU 3420 AGUCCCAGGAUUGGCCAGC3421 CUGGCCAAUCCUGGGACUC 3422 GAGUCCCAGGAUUGGCCAG 3423UGGCCAAUCCUGGGACUCA 3424 UGAGUCCCAGGAUUGGCCA 3425 AUCCUGGGACUCAGAGGGU3426 ACCCUCUGAGUCCCAGGAU 3427 UCCUGGGACUCAGAGGGUA 3428UACCCUCUGAGUCCCAGGA 3429 CCUGGGACUCAGAGGGUAG 3430 CUACCCUCUGAGUCCCAGG3431 CUGGGACUCAGAGGGUAGG 3432 CCUACCCUCUGAGUCCCAG 3433GGACUCAGAGGGUAGGUCG 3434 CGACCUACCCUCUGAGUCC 3435 GACUCAGAGGGUAGGUCGG3436 CCGACCUACCCUCUGAGUC 3437 ACUCAGAGGGUAGGUCGGC 3438GCCGACCUACCCUCUGAGU 3439 CUCAGAGGGUAGGUCGGCU 3440 AGCCGACCUACCCUCUGAG3441 UCAGAGGGUAGGUCGGCUG 3442 CAGCCGACCUACCCUCUGA 3443GGCUGGCUGACCACUAGGU 3444 ACCUAGUGGUCAGCCAGCC 3445 GCUGGCUGACCACUAGGUU3446 AACCUAGUGGUCAGCCAGC 3447 CUGGCUGACCACUAGGUUU 3448AAACCUAGUGGUCAGCCAG 3449 CUGACCACUAGGUUUGGAA 3450 UUCCAAACCUAGUGGUCAG3451 UGACCACUAGGUUUGGAAG 3452 CUUCCAAACCUAGUGGUCA 3453GACCACUAGGUUUGGAAGA 3454 UCUUCCAAACCUAGUGGUC 3455 ACCACUAGGUUUGGAAGAC3456 GUCUUCCAAACCUAGUGGU 3457 CCACUAGGUUUGGAAGACC 3458GGUCUUCCAAACCUAGUGG 3459 UAGGUUUGGAAGACCCAGG 3460 CCUGGGUCUUCCAAACCUA3461 AGGUUUGGAAGACCCAGGC 3462 GCCUGGGUCUUCCAAACCU 3463CAGGCAGCUGGCUCUAAAG 3464 CUUUAGAGCCAGCUGCCUG 3465 AGGCAGCUGGCUCUAAAGA3466 UCUUUAGAGCCAGCUGCCU 3467 AGCUGGCUCUAAAGAGGCC 3468GGCCUCUUUAGAGCCAGCU 3469 GCUGGCUCUAAAGAGGCCC 3470 GGGCCUCUUUAGAGCCAGC3471 CCAGGUCAGUAGCCAGACA 3472 UGUCUGGCUACUGACCUGG 3473GUCAGUAGCCAGACAUGAG 3474 CUCAUGUCUGGCUACUGAC 3475 GUAGCCAGACAUGAGCUGU3476 ACAGCUCAUGUCUGGCUAC 3477 AGACAUGAGCUGUGAGGGU 3478ACCCUCACAGCUCAUGUCU 3479 AUGAGCUGUGAGGGUCAAG 3480 CUUGACCCUCACAGCUCAU3481 UGAGCUGUGAGGGUCAAGC 3482 GCUUGACCCUCACAGCUCA 3483GAGCUGUGAGGGUCAAGCA 3484 UGCUUGACCCUCACAGCUC 3485 AGCUGUGAGGGUCAAGCAC3486 GUGCUUGACCCUCACAGCU 3487 GUGAGGGUCAAGCACAGCU 3488AGCUGUGCUUGACCCUCAC 3489 UGAGGGUCAAGCACAGCUA 3490 UAGCUGUGCUUGACCCUCA3491 GAGGGUCAAGCACAGCUAU 3492 AUAGCUGUGCUUGACCCUC 3493AGGGUCAAGCACAGCUAUC 3494 GAUAGCUGUGCUUGACCCU 3495 GGGUCAAGCACAGCUAUCC3496 GGAUAGCUGUGCUUGACCC 3497 CAAGCACAGCUAUCCAUCA 3498UGAUGGAUAGCUGUGCUUG 3499 CACAGCUAUCCAUCAGAUG 3500 CAUCUGAUGGAUAGCUGUG3501 ACAGCUAUCCAUCAGAUGA 3502 UCAUCUGAUGGAUAGCUGU 3503CAGCUAUCCAUCAGAUGAU 3504 AUCAUCUGAUGGAUAGCUG 3505 AGCUAUCCAUCAGAUGAUC3506 GAUCAUCUGAUGGAUAGCU 3507 GCUAUCCAUCAGAUGAUCU 3508AGAUCAUCUGAUGGAUAGC 3509 CUAUCCAUCAGAUGAUCUA 3510 UAGAUCAUCUGAUGGAUAG3511 CAUCAGAUGAUCUACUUUC 3512 GAAAGUAGAUCAUCUGAUG 3513AGAUGAUCUACUUUCAGCC 3514 GGCUGAAAGUAGAUCAUCU 3515 GAUCUACUUUCAGCCUUCC3516 GGAAGGCUGAAAGUAGAUC 3517 AUCUACUUUCAGCCUUCCU 3518AGGAAGGCUGAAAGUAGAU 3519 CAAUAGAAGACAGGUGGCU 3520 AGCCACCUGUCUUCUAUUG3521 AAUAGAAGACAGGUGGCUG 3522 CAGCCACCUGUCUUCUAUU 3523CAGGUGGCUGUACCCUUGG 3524 CCAAGGGUACAGCCACCUG 3525 AGGUGGCUGUACCCUUGGC3526 GCCAAGGGUACAGCCACCU 3527 GGCUGUACCCUUGGCCAAG 3528CUUGGCCAAGGGUACAGCC 3529 UGGUGUCUGCUGUCACUGU 3530 ACAGUGACAGCAGACACCA3531 GUCUGCUGUCACUGUGCCC 3532 GGGCACAGUGACAGCAGAC 3533CUGCUGUCACUGUGCCCUC 3534 GAGGGCACAGUGACAGCAG 3535 UGCUGUCACUGUGCCCUCA3536 UGAGGGCACAGUGACAGCA 3537 GCUGUCACUGUGCCCUCAU 3538AUGAGGGCACAGUGACAGC 3539 CUGUCACUGUGCCCUCAUU 3540 AAUGAGGGCACAGUGACAG3541 UGUCACUGUGCCCUCAUUG 3542 CAAUGAGGGCACAGUGACA 3543GUCACUGUGCCCUCAUUGG 3544 CCAAUGAGGGCACAGUGAC 3545 ACUGUGCCCUCAUUGGCCC3546 GGGCCAAUGAGGGCACAGU 3547 CCCAGCAAUCAGACUCAAC 3548GUUGAGUCUGAUUGCUGGG 3549 GGAGCAACUGCCAUCCGAG 3550 CUCGGAUGGCAGUUGCUCC3551 GAGCAACUGCCAUCCGAGG 3552 CCUCGGAUGGCAGUUGCUC 3553AGCAACUGCCAUCCGAGGC 3554 GCCUCGGAUGGCAGUUGCU 3555 GCAACUGCCAUCCGAGGCU3556 AGCCUCGGAUGGCAGUUGC 3557 CAACUGCCAUCCGAGGCUC 3558GAGCCUCGGAUGGCAGUUG 3559 GCCAUCCGAGGCUCCUGAA 3560 UUCAGGAGCCUCGGAUGGC3561 AACCAGGGCCAUUCACCAG 3562 CUGGUGAAUGGCCCUGGUU 3563ACCAGGGCCAUUCACCAGG 3564 CCUGGUGAAUGGCCCUGGU 3565 CCAGGGCCAUUCACCAGGA3566 UCCUGGUGAAUGGCCCUGG 3567 CAGGGCCAUUCACCAGGAG 3568CUCCUGGUGAAUGGCCCUG 3569 GGCCAUUCACCAGGAGCAU 3570 AUGCUCCUGGUGAAUGGCC3571 GCCAUUCACCAGGAGCAUG 3572 CAUGCUCCUGGUGAAUGGC 3573CCAUUCACCAGGAGCAUGC 3574 GCAUGCUCCUGGUGAAUGG 3575 CAUUCACCAGGAGCAUGCG3576 CGCAUGCUCCUGGUGAAUG 3577 AUUCACCAGGAGCAUGCGG 3578CCGCAUGCUCCUGGUGAAU 3579 UUCACCAGGAGCAUGCGGC 3580 GCCGCAUGCUCCUGGUGAA3581 UCACCAGGAGCAUGCGGCU 3582 AGCCGCAUGCUCCUGGUGA 3583AGCAUGCGGCUCCCUGAUG 3584 CAUCAGGGAGCCGCAUGCU 3585 GCAUGCGGCUCCCUGAUGU3586 ACAUCAGGGAGCCGCAUGC 3587 CAUGCGGCUCCCUGAUGUC 3588GACAUCAGGGAGCCGCAUG 3589 AUGCGGCUCCCUGAUGUCC 3590 GGACAUCAGGGAGCCGCAU3591 UGCGGCUCCCUGAUGUCCA 3592 UGGACAUCAGGGAGCCGCA 3593GCUCCCUGAUGUCCAGCUC 3594 GAGCUGGACAUCAGGGAGC 3595 CUCCCUGAUGUCCAGCUCU3596 AGAGCUGGACAUCAGGGAG 3597 UCCCUGAUGUCCAGCUCUG 3598CAGAGCUGGACAUCAGGGA 3599 CCCUGAUGUCCAGCUCUGG 3600 CCAGAGCUGGACAUCAGGG3601 CCUGAUGUCCAGCUCUGGC 3602 GCCAGAGCUGGACAUCAGG 3603CUGAUGUCCAGCUCUGGCU 3604 AGCCAGAGCUGGACAUCAG 3605 UCUGGUGCUGGAGCUAGCC3606 GGCUAGCUCCAGCACCAGA 3607 UGGUGCUGGAGCUAGCCAA 3608UUGGCUAGCUCCAGCACCA 3609 GGUGCUGGAGCUAGCCAAG 3610 CUUGGCUAGCUCCAGCACC3611 GUGCUGGAGCUAGCCAAGC 3612 GCUUGGCUAGCUCCAGCAC 3613GCUGGAGCUAGCCAAGCAG 3614 CUGCUUGGCUAGCUCCAGC 3615 CUGGAGCUAGCCAAGCAGC3616 GCUGCUUGGCUAGCUCCAG 3617 UGGAGCUAGCCAAGCAGCA 3618UGCUGCUUGGCUAGCUCCA 3619 GGAGCUAGCCAAGCAGCAA 3620 UUGCUGCUUGGCUAGCUCC3621 GAGCUAGCCAAGCAGCAAA 3622 UUUGCUGCUUGGCUAGCUC 3623AGCUAGCCAAGCAGCAAAU 3624 AUUUGCUGCUUGGCUAGCU 3625 GCUAGCCAAGCAGCAAAUC3626 GAUUUGCUGCUUGGCUAGC 3627 CAGCAAAUCCUGGAUGGGU 3628ACCCAUCCAGGAUUUGCUG 3629 AGCAAAUCCUGGAUGGGUU 3630 AACCCAUCCAGGAUUUGCU3631 GCAAAUCCUGGAUGGGUUG 3632 CAACCCAUCCAGGAUUUGC 3633CAAAUCCUGGAUGGGUUGC 3634 GCAACCCAUCCAGGAUUUG 3635 AAAUCCUGGAUGGGUUGCA3636 UGCAACCCAUCCAGGAUUU 3637 GGUUGCACCUGACCAGUCG 3638CGACUGGUCAGGUGCAACC 3639 GUUGCACCUGACCAGUCGU 3640 ACGACUGGUCAGGUGCAAC3641 UUGCACCUGACCAGUCGUC 3642 GACGACUGGUCAGGUGCAA 3643UGCACCUGACCAGUCGUCC 3644 GGACGACUGGUCAGGUGCA 3645 UGACCAGUCGUCCCAGAAU3646 AUUCUGGGACGACUGGUCA 3647 GACCAGUCGUCCCAGAAUA 3648UAUUCUGGGACGACUGGUC 3649 ACCAGUCGUCCCAGAAUAA 3650 UUAUUCUGGGACGACUGGU3651 CCAGUCGUCCCAGAAUAAC 3652 GUUAUUCUGGGACGACUGG 3653CAGUCGUCCCAGAAUAACU 3654 AGUUAUUCUGGGACGACUG 3655 AGUCGUCCCAGAAUAACUC3656 GAGUUAUUCUGGGACGACU 3657 GUCGUCCCAGAAUAACUCA 3658UGAGUUAUUCUGGGACGAC 3659 UCGUCCCAGAAUAACUCAU 3660 AUGAGUUAUUCUGGGACGA3661 CGUCCCAGAAUAACUCAUC 3662 GAUGAGUUAUUCUGGGACG 3663GUCCCAGAAUAACUCAUCC 3664 GGAUGAGUUAUUCUGGGAC 3665 UCCCAGAAUAACUCAUCCU3666 AGGAUGAGUUAUUCUGGGA 3667 CCCAGAAUAACUCAUCCUC 3668GAGGAUGAGUUAUUCUGGG 3669 GACUACAGCCAGGGAGUGU 3670 ACACUCCCUGGCUGUAGUC3671 ACUACAGCCAGGGAGUGUG 3672 CACACUCCCUGGCUGUAGU 3673CUACAGCCAGGGAGUGUGG 3674 CCACACUCCCUGGCUGUAG 3675 GAGUGUGGCUCCAGGGAAU3676 AUUCCCUGGAGCCACACUC 3677 GGGAGGAGGUCAUCAGCUU 3678AAGCUGAUGACCUCCUCCC 3679 GAGGUCAUCAGCUUUGCUA 3680 UAGCAAAGCUGAUGACCUC3681 AGGUCAUCAGCUUUGCUAC 3682 GUAGCAAAGCUGAUGACCU 3683GGUCAUCAGCUUUGCUACU 3684 AGUAGCAAAGCUGAUGACC 3685 GCUUUGCUACUGUCACAGG3686 CCUGUGACAGUAGCAAAGC 3687 CUUUGCUACUGUCACAGGU 3688ACCUGUGACAGUAGCAAAG 3689 UUUGCUACUGUCACAGGUG 3690 CACCUGUGACAGUAGCAAA3691 UUGCUACUGUCACAGGUGG 3692 CCACCUGUGACAGUAGCAA 3693UGCUACUGUCACAGGUGGG 3694 CCCACCUGUGACAGUAGCA 3695 GCUACUGUCACAGGUGGGU3696 ACCCACCUGUGACAGUAGC 3697 CUACUGUCACAGGUGGGUG 3698CACCCACCUGUGACAGUAG 3699 CAGGCAAAGAGCAGACAGG 3700 CCUGUCUGCUCUUUGCCUG3701 GGCAGGGACUGGUUGCAGA 3702 UCUGCAACCAGUCCCUGCC 3703GCAGGGACUGGUUGCAGAG 3704 CUCUGCAACCAGUCCCUGC 3705 AGGGACUGGUUGCAGAGGA3706 UCCUCUGCAACCAGUCCCU 3707 GGGACUGGUUGCAGAGGAC 3708GUCCUCUGCAACCAGUCCC 3709 GGACUGGUUGCAGAGGACA 3710 UGUCCUCUGCAACCAGUCC3711 GACUGGUUGCAGAGGACAC 3712 GUGUCCUCUGCAACCAGUC 3713UUUUCUAGAGGUAGGUUCG 3714 CGAACCUACCUCUAGAAAA 3715 UUUCUAGAGGUAGGUUCGA3716 UCGAACCUACCUCUAGAAA 3717 UUCUAGAGGUAGGUUCGAG 3718CUCGAACCUACCUCUAGAA 3719 UCUAGAGGUAGGUUCGAGG 3720 CCUCGAACCUACCUCUAGA3721 CUAGAGGUAGGUUCGAGGG 3722 CCCUCGAACCUACCUCUAG 3723UAGAGGUAGGUUCGAGGGA 3724 UCCCUCGAACCUACCUCUA 3725 GAGCUUCAUCUCUACUCAC3726 GUGAGUAGAGAUGAAGCUC 3727 AGCUUCAUCUCUACUCACA 3728UGUGAGUAGAGAUGAAGCU 3729 GCUUCAUCUCUACUCACAU 3730 AUGUGAGUAGAGAUGAAGC3731 CUUCAUCUCUACUCACAUU 3732 AAUGUGAGUAGAGAUGAAG 3733AUCUCUACUCACAUUUUCU 3734 AGAAAAUGUGAGUAGAGAU 3735 UCUCUACUCACAUUUUCUU3736 AAGAAAAUGUGAGUAGAGA 3737 UCACAUUUUCUUUCCCUUU 3738AAAGGGAAAGAAAAUGUGA 3739 CCCUUUUCUGUCUUUCGGG 3740 CCCGAAAGACAGAAAAGGG3741 CCUUUUCUGUCUUUCGGGC 3742 GCCCGAAAGACAGAAAAGG 3743CUUUUCUGUCUUUCGGGCA 3744 UGCCCGAAAGACAGAAAAG 3745 UUUCGGGCAGACUCCACUU3746 AAGUGGAGUCUGCCCGAAA 3747 UUCGGGCAGACUCCACUUC 3748GAAGUGGAGUCUGCCCGAA 3749 UCGGGCAGACUCCACUUCA 3750 UGAAGUGGAGUCUGCCCGA3751 CGGGCAGACUCCACUUCAG 3752 CUGAAGUGGAGUCUGCCCG 3753GGGCAGACUCCACUUCAGC 3754 GCUGAAGUGGAGUCUGCCC 3755 GGCAGACUCCACUUCAGCC3756 GGCUGAAGUGGAGUCUGCC 3757 UCCACUUCAGCCUACAGCU 3758AGCUGUAGGCUGAAGUGGA 3759 CCACUUCAGCCUACAGCUC 3760 GAGCUGUAGGCUGAAGUGG3761 CACUUCAGCCUACAGCUCC 3762 GGAGCUGUAGGCUGAAGUG 3763ACUUCAGCCUACAGCUCCC 3764 GGGAGCUGUAGGCUGAAGU 3765 CCUACAGCUCCCUGCUCAC3766 GUGAGCAGGGAGCUGUAGG 3767 CUACAGCUCCCUGCUCACU 3768AGUGAGCAGGGAGCUGUAG 3769 UACAGCUCCCUGCUCACUU 3770 AAGUGAGCAGGGAGCUGUA3771 GCUCCCUGCUCACUUUUCA 3772 UGAAAAGUGAGCAGGGAGC 3773CUCCCUGCUCACUUUUCAC 3774 GUGAAAAGUGAGCAGGGAG 3775 GCUCACUUUUCACCUGUCC3776 GGACAGGUGAAAAGUGAGC 3777 CUCACUUUUCACCUGUCCA 3778UGGACAGGUGAAAAGUGAG 3779 UGUCCACUCCUCGGUCCCA 3780 UGGGACCGAGGAGUGGACA3781 UCGGUCCCACCACCUGUAC 3782 GUACAGGUGGUGGGACCGA 3783CCACCACCUGUACCAUGCC 3784 GGCAUGGUACAGGUGGUGG 3785 CACCACCUGUACCAUGCCC3786 GGGCAUGGUACAGGUGGUG 3787 ACCACCUGUACCAUGCCCG 3788CGGGCAUGGUACAGGUGGU 3789 CACCCUUCCUGGCACUCUU 3790 AAGAGUGCCAGGAAGGGUG3791 ACCCUUCCUGGCACUCUUU 3792 AAAGAGUGCCAGGAAGGGU 3793CCCUUCCUGGCACUCUUUG 3794 CAAAGAGUGCCAGGAAGGG 3795 CCUUCCUGGCACUCUUUGC3796 GCAAAGAGUGCCAGGAAGG 3797 UUCCUGGCACUCUUUGCUU 3798AAGCAAAGAGUGCCAGGAA 3799 UCCUGGCACUCUUUGCUUG 3800 CAAGCAAAGAGUGCCAGGA3801 CCUGGCACUCUUUGCUUGA 3802 UCAAGCAAAGAGUGCCAGG 3803CUGGCACUCUUUGCUUGAG 3804 CUCAAGCAAAGAGUGCCAG 3805 UGGCACUCUUUGCUUGAGG3806 CCUCAAGCAAAGAGUGCCA 3807 GGCACUCUUUGCUUGAGGA 3808UCCUCAAGCAAAGAGUGCC 3809 GCACUCUUUGCUUGAGGAU 3810 AUCCUCAAGCAAAGAGUGC3811 CACUCUUUGCUUGAGGAUC 3812 GAUCCUCAAGCAAAGAGUG 3813ACUCUUUGCUUGAGGAUCU 3814 AGAUCCUCAAGCAAAGAGU 3815 CUCUUUGCUUGAGGAUCUU3816 AAGAUCCUCAAGCAAAGAG 3817 UCUUUGCUUGAGGAUCUUC 3818GAAGAUCCUCAAGCAAAGA 3819 UGCUUGAGGAUCUUCCGAU 3820 AUCGGAAGAUCCUCAAGCA3821 GCUUGAGGAUCUUCCGAUG 3822 CAUCGGAAGAUCCUCAAGC 3823GCACUCUCCUGGCUGAGCA 3824 UGCUCAGCCAGGAGAGUGC 3825 CUCCUGGCUGAGCACCACA3826 UGUGGUGCUCAGCCAGGAG 3827 UGGCUGAGCACCACAUCAC 3828GUGAUGUGGUGCUCAGCCA 3829 GGCUGAGCACCACAUCACC 3830 GGUGAUGUGGUGCUCAGCC3831 GCUGAGCACCACAUCACCA 3832 UGGUGAUGUGGUGCUCAGC 3833CUGAGCACCACAUCACCAA 3834 UUGGUGAUGUGGUGCUCAG 3835 CCAACCUGGGCUGGCAUAC3836 GUAUGCCAGCCCAGGUUGG 3837 CAACCUGGGCUGGCAUACC 3838GGUAUGCCAGCCCAGGUUG 3839 AACCUGGGCUGGCAUACCU 3840 AGGUAUGCCAGCCCAGGUU3841 ACCUGGGCUGGCAUACCUU 3842 AAGGUAUGCCAGCCCAGGU 3843CCUGGGCUGGCAUACCUUA 3844 UAAGGUAUGCCAGCCCAGG 3845 CUGGGCUGGCAUACCUUAA3846 UUAAGGUAUGCCAGCCCAG 3847 UGGGCUGGCAUACCUUAAC 3848GUUAAGGUAUGCCAGCCCA 3849 GGGCUGGCAUACCUUAACU 3850 AGUUAAGGUAUGCCAGCCC3851 GGCUGGCAUACCUUAACUC 3852 GAGUUAAGGUAUGCCAGCC 3853GCUGGCAUACCUUAACUCU 3854 AGAGUUAAGGUAUGCCAGC 3855 CAUACCUUAACUCUGCCCU3856 AGGGCAGAGUUAAGGUAUG 3857 AUACCUUAACUCUGCCCUC 3858GAGGGCAGAGUUAAGGUAU 3859 UACCUUAACUCUGCCCUCU 3860 AGAGGGCAGAGUUAAGGUA3861 UCUGCCCUCUAGUGGCUUG 3862 CAAGCCACUAGAGGGCAGA 3863CUGCCCUCUAGUGGCUUGA 3864 UCAAGCCACUAGAGGGCAG 3865 UGCCCUCUAGUGGCUUGAG3866 CUCAAGCCACUAGAGGGCA 3867 AGAAGUCUGGUGUCCUGAA 3868UUCAGGACACCAGACUUCU 3869 CAGGACACCAGCAGCCCUU 3870 AAGGGCUGCUGGUGUCCUG3871 AGGACACCAGCAGCCCUUC 3872 GAAGGGCUGCUGGUGUCCU 3873ACACCAGCAGCCCUUCCUA 3874 UAGGAAGGGCUGCUGGUGU 3875 CACCAGCAGCCCUUCCUAG3876 CUAGGAAGGGCUGCUGGUG 3877 ACCAGCAGCCCUUCCUAGA 3878UCUAGGAAGGGCUGCUGGU 3879 CCAGCAGCCCUUCCUAGAG 3880 CUCUAGGAAGGGCUGCUGG3881 CAGCAGCCCUUCCUAGAGC 3882 GCUCUAGGAAGGGCUGCUG 3883AGCAGCCCUUCCUAGAGCU 3884 AGCUCUAGGAAGGGCUGCU 3885 GCCCUUCCUAGAGCUUAAG3886 CUUAAGCUCUAGGAAGGGC 3887 CCCUUCCUAGAGCUUAAGA 3888UCUUAAGCUCUAGGAAGGG 3889 AGCUUAAGAUCCGAGCCAA 3890 UUGGCUCGGAUCUUAAGCU3891 GCUUAAGAUCCGAGCCAAU 3892 AUUGGCUCGGAUCUUAAGC 3893CUUAAGAUCCGAGCCAAUG 3894 CAUUGGCUCGGAUCUUAAG 3895 UUAAGAUCCGAGCCAAUGA3896 UCAUUGGCUCGGAUCUUAA 3897 UAAGAUCCGAGCCAAUGAG 3898CUCAUUGGCUCGGAUCUUA 3899 CGAGCCAAUGAGCCUGGAG 3900 CUCCAGGCUCAUUGGCUCG3901 CCCUUAUGUUGCAGGCGAG 3902 CUCGCCUGCAACAUAAGGG 3903CAUUACGUAGACUUCCAGG 3904 CCUGGAAGUCUACGUAAUG 3905 AUUACGUAGACUUCCAGGA3906 UCCUGGAAGUCUACGUAAU 3907 UUACGUAGACUUCCAGGAA 3908UUCCUGGAAGUCUACGUAA 3909 ACUGGAUACUGCAGCCCGA 3910 UCGGGCUGCAGUAUCCAGU3911 CUGGAUACUGCAGCCCGAG 3912 CUCGGGCUGCAGUAUCCAG 3913UGGAUACUGCAGCCCGAGG 3914 CCUCGGGCUGCAGUAUCCA 3915 GGGUACCAGCUGAAUUACU3916 AGUAAUUCAGCUGGUACCC 3917 CUGAAUUACUGCAGUGGGC 3918GCCCACUGCAGUAAUUCAG 3919 UGAAUUACUGCAGUGGGCA 3920 UGCCCACUGCAGUAAUUCA3921 UGGCAGCCCAGGCAUUGCU 3922 AGCAAUGCCUGGGCUGCCA 3923GCAUUGCUGCCUCUUUCCA 3924 UGGAAAGAGGCAGCAAUGC 3925 CAUUGCUGCCUCUUUCCAU3926 AUGGAAAGAGGCAGCAAUG 3927 AUUGCUGCCUCUUUCCAUU 3928AAUGGAAAGAGGCAGCAAU 3929 UGCUGCCUCUUUCCAUUCU 3930 AGAAUGGAAAGAGGCAGCA3931 GCUGCCUCUUUCCAUUCUG 3932 CAGAAUGGAAAGAGGCAGC 3933CUGCCUCUUUCCAUUCUGC 3934 GCAGAAUGGAAAGAGGCAG 3935 UGCCUCUUUCCAUUCUGCC3936 GGCAGAAUGGAAAGAGGCA 3937 GCCUCUUUCCAUUCUGCCG 3938CGGCAGAAUGGAAAGAGGC 3939 CCUCUUUCCAUUCUGCCGU 3940 ACGGCAGAAUGGAAAGAGG3941 CUCUUUCCAUUCUGCCGUC 3942 GACGGCAGAAUGGAAAGAG 3943CAUUCUGCCGUCUUCAGCC 3944 GGCUGAAGACGGCAGAAUG 3945 CUUCAGCCUCCUCAAAGCC3946 GGCUUUGAGGAGGCUGAAG 3947 UUCAGCCUCCUCAAAGCCA 3948UGGCUUUGAGGAGGCUGAA 3949 UCAGCCUCCUCAAAGCCAA 3950 UUGGCUUUGAGGAGGCUGA3951 CAGCCUCCUCAAAGCCAAC 3952 GUUGGCUUUGAGGAGGCUG 3953UCCUUGGCCUGCCAGUACC 3954 GGUACUGGCAGGCCAAGGA 3955 CCUGCCAGUACCUCCUGUU3956 AACAGGAGGUACUGGCAGG 3957 CUGCCAGUACCUCCUGUUG 3958CAACAGGAGGUACUGGCAG 3959 UGCCAGUACCUCCUGUUGU 3960 ACAACAGGAGGUACUGGCA3961 GCCAGUACCUCCUGUUGUG 3962 CACAACAGGAGGUACUGGC 3963CCAGUACCUCCUGUUGUGU 3964 ACACAACAGGAGGUACUGG 3965 CAGUACCUCCUGUUGUGUC3966 GACACAACAGGAGGUACUG 3967 GUACCUCCUGUUGUGUCCC 3968GGGACACAACAGGAGGUAC 3969 UACCUCCUGUUGUGUCCCU 3970 AGGGACACAACAGGAGGUA3971 ACCUCCUGUUGUGUCCCUA 3972 UAGGGACACAACAGGAGGU 3973CCUCCUGUUGUGUCCCUAC 3974 GUAGGGACACAACAGGAGG 3975 CUCCUGUUGUGUCCCUACU3976 AGUAGGGACACAACAGGAG 3977 UUGUGUCCCUACUGCCCGA 3978UCGGGCAGUAGGGACACAA 3979 UGUGUCCCUACUGCCCGAA 3980 UUCGGGCAGUAGGGACACA3981 GUGUCCCUACUGCCCGAAG 3982 CUUCGGGCAGUAGGGACAC 3983UGUCCCUACUGCCCGAAGG 3984 CCUUCGGGCAGUAGGGACA 3985 UCUCUCUCCUCUACCUGGA3986 UCCAGGUAGAGGAGAGAGA 3987 UCUCCUCUACCUGGAUCAU 3988AUGAUCCAGGUAGAGGAGA 3989 CUCCUCUACCUGGAUCAUA 3990 UAUGAUCCAGGUAGAGGAG3991 UCCUCUACCUGGAUCAUAA 3992 UUAUGAUCCAGGUAGAGGA 3993CCUCUACCUGGAUCAUAAU 3994 AUUAUGAUCCAGGUAGAGG 3995 CUCUACCUGGAUCAUAAUG3996 CAUUAUGAUCCAGGUAGAG 3997 UCUACCUGGAUCAUAAUGG 3998CCAUUAUGAUCCAGGUAGA 3999 CUACCUGGAUCAUAAUGGC 4000 GCCAUUAUGAUCCAGGUAG4001 UACCUGGAUCAUAAUGGCA 4002 UGCCAUUAUGAUCCAGGUA 4003ACCUGGAUCAUAAUGGCAA 4004 UUGCCAUUAUGAUCCAGGU 4005 CCUGGAUCAUAAUGGCAAU4006 AUUGCCAUUAUGAUCCAGG 4007 CUGGAUCAUAAUGGCAAUG 4008CAUUGCCAUUAUGAUCCAG 4009 UGGAUCAUAAUGGCAAUGU 4010 ACAUUGCCAUUAUGAUCCA4011 GGAUCAUAAUGGCAAUGUG 4012 CACAUUGCCAUUAUGAUCC 4013GAUCAUAAUGGCAAUGUGG 4014 CCACAUUGCCAUUAUGAUC 4015 AUAAUGGCAAUGUGGUCAA4016 UUGACCACAUUGCCAUUAU 4017 UAAUGGCAAUGUGGUCAAG 4018CUUGACCACAUUGCCAUUA 4019 AAUGGCAAUGUGGUCAAGA 4020 UCUUGACCACAUUGCCAUU4021 AAUGUGGUCAAGACGGAUG 4022 CAUCCGUCUUGACCACAUU 4023AUGUGGUCAAGACGGAUGU 4024 ACAUCCGUCUUGACCACAU 4025 UGUGGUCAAGACGGAUGUG4026 CACAUCCGUCUUGACCACA 4027 GUGGUCAAGACGGAUGUGC 4028GCACAUCCGUCUUGACCAC 4029 UGGUCAAGACGGAUGUGCC 4030 GGCACAUCCGUCUUGACCA4031 GGUCAAGACGGAUGUGCCA 4032 UGGCACAUCCGUCUUGACC 4033GUCAAGACGGAUGUGCCAG 4034 CUGGCACAUCCGUCUUGAC 4035 UCAAGACGGAUGUGCCAGA4036 UCUGGCACAUCCGUCUUGA 4037 CAAGACGGAUGUGCCAGAU 4038AUCUGGCACAUCCGUCUUG 4039 AAGACGGAUGUGCCAGAUA 4040 UAUCUGGCACAUCCGUCUU4041 AGACGGAUGUGCCAGAUAU 4042 AUAUCUGGCACAUCCGUCU 4043GACGGAUGUGCCAGAUAUG 4044 CAUAUCUGGCACAUCCGUC 4045 ACGGAUGUGCCAGAUAUGG4046 CCAUAUCUGGCACAUCCGU 4047 CGGAUGUGCCAGAUAUGGU 4048ACCAUAUCUGGCACAUCCG 4049 GGAUGUGCCAGAUAUGGUG 4050 CACCAUAUCUGGCACAUCC4051 GAUGUGCCAGAUAUGGUGG 4052 CCACCAUAUCUGGCACAUC 4053GCCAGAUAUGGUGGUGGAG 4054 CUCCACCACCAUAUCUGGC 4055 CCAGAUAUGGUGGUGGAGG4056 CCUCCACCACCAUAUCUGG 4057 CAGAUAUGGUGGUGGAGGC 4058GCCUCCACCACCAUAUCUG 4059 AGAUAUGGUGGUGGAGGCC 4060 GGCCUCCACCACCAUAUCU4061 GAUAUGGUGGUGGAGGCCU 4062 AGGCCUCCACCACCAUAUC 4063AUAUGGUGGUGGAGGCCUG 4064 CAGGCCUCCACCACCAUAU 4065 CCUGUGGCUGCAGCUAGCA4066 UGCUAGCUGCAGCCACAGG 4067 UGUGGCUGCAGCUAGCAAG 4068CUUGCUAGCUGCAGCCACA 4069 GUGGCUGCAGCUAGCAAGA 4070 UCUUGCUAGCUGCAGCCAC4071 UGGCUGCAGCUAGCAAGAG 4072 CUCUUGCUAGCUGCAGCCA 4073GGCUGCAGCUAGCAAGAGG 4074 CCUCUUGCUAGCUGCAGCC 4075 CUGCAGCUAGCAAGAGGAC4076 GUCCUCUUGCUAGCUGCAG 4077 CAGCUAGCAAGAGGACCUG 4078CAGGUCCUCUUGCUAGCUG 4079 GCUAGCAAGAGGACCUGGG 4080 CCCAGGUCCUCUUGCUAGC4081 AGACCAAGAUGAAGUUUCC 4082 GGAAACUUCAUCUUGGUCU 4083UGAAGUUUCCCAGGCACAG 4084 CUGUGCCUGGGAAACUUCA 4085 GAAGUUUCCCAGGCACAGG4086 CCUGUGCCUGGGAAACUUC 4087 UCCCAGGCACAGGGCAUCU 4088AGAUGCCCUGUGCCUGGGA 4089 GGCAUCUGUGACUGGAGGC 4090 GCCUCCAGUCACAGAUGCC4091 GCAUCUGUGACUGGAGGCA 4092 UGCCUCCAGUCACAGAUGC 4093CAACCACCUGGCAAUAUGA 4094 UCAUAUUGCCAGGUGGUUG 4095 AACCACCUGGCAAUAUGAC4096 GUCAUAUUGCCAGGUGGUU 4097 ACCACCUGGCAAUAUGACU 4098AGUCAUAUUGCCAGGUGGU 4099 CCACCUGGCAAUAUGACUC 4100 GAGUCAUAUUGCCAGGUGG4101 CACCUGGCAAUAUGACUCA 4102 UGAGUCAUAUUGCCAGGUG 4103ACCUGGCAAUAUGACUCAC 4104 GUGAGUCAUAUUGCCAGGU 4105 CCUGGCAAUAUGACUCACU4106 AGUGAGUCAUAUUGCCAGG 4107 CUGGCAAUAUGACUCACUU 4108AAGUGAGUCAUAUUGCCAG 4109 UGGCAAUAUGACUCACUUG 4110 CAAGUGAGUCAUAUUGCCA4111 AAUAUGACUCACUUGACCC 4112 GGGUCAAGUGAGUCAUAUU 4113CCCUAUGGGACCCAAAUGG 4114 CCAUUUGGGUCCCAUAGGG 4115 CCUAUGGGACCCAAAUGGG4116 CCCAUUUGGGUCCCAUAGG 4117 CUAUGGGACCCAAAUGGGC 4118GCCCAUUUGGGUCCCAUAG 4119 UAUGGGACCCAAAUGGGCA 4120 UGCCCAUUUGGGUCCCAUA4121 AUGGGACCCAAAUGGGCAC 4122 GUGCCCAUUUGGGUCCCAU 4123CCCAAAUGGGCACUUUCUU 4124 AAGAAAGUGCCCAUUUGGG 4125 CCAAAUGGGCACUUUCUUG4126 CAAGAAAGUGCCCAUUUGG 4127 CAAAUGGGCACUUUCUUGU 4128ACAAGAAAGUGCCCAUUUG 4129 AAAUGGGCACUUUCUUGUC 4130 GACAAGAAAGUGCCCAUUU4131 AAUGGGCACUUUCUUGUCU 4132 AGACAAGAAAGUGCCCAUU 4133UGGGCACUUUCUUGUCUGA 4134 UCAGACAAGAAAGUGCCCA 4135 GGGCACUUUCUUGUCUGAG4136 CUCAGACAAGAAAGUGCCC 4137 UGGCUUAUUCCAGGUUGGC 4138GCCAACCUGGAAUAAGCCA 4139 GGCUUAUUCCAGGUUGGCU 4140 AGCCAACCUGGAAUAAGCC4141 GCUUAUUCCAGGUUGGCUG 4142 CAGCCAACCUGGAAUAAGC 4143CUUAUUCCAGGUUGGCUGA 4144 UCAGCCAACCUGGAAUAAG 4145 UUCCAGGUUGGCUGAUGUG4146 CACAUCAGCCAACCUGGAA 4147 UCCAGGUUGGCUGAUGUGU 4148ACACAUCAGCCAACCUGGA 4149 CCAGGUUGGCUGAUGUGUU 4150 AACACAUCAGCCAACCUGG4151 CAGGUUGGCUGAUGUGUUG 4152 CAACACAUCAGCCAACCUG 4153AGGUUGGCUGAUGUGUUGG 4154 CCAACACAUCAGCCAACCU 4155 GGUUGGCUGAUGUGUUGGG4156 CCCAACACAUCAGCCAACC 4157 AGAUGGGUAAAGCGUUUCU 4158AGAAACGCUUUACCCAUCU 4159 GAUGGGUAAAGCGUUUCUU 4160 AAGAAACGCUUUACCCAUC4161 AUGGGUAAAGCGUUUCUUC 4162 GAAGAAACGCUUUACCCAU 4163UGGGUAAAGCGUUUCUUCU 4164 AGAAGAAACGCUUUACCCA 4165 GGGUAAAGCGUUUCUUCUA4166 UAGAAGAAACGCUUUACCC 4167 GGUAAAGCGUUUCUUCUAA 4168UUAGAAGAAACGCUUUACC 4169 GUAAAGCGUUUCUUCUAAA 4170 UUUAGAAGAAACGCUUUAC4171 UAAAGCGUUUCUUCUAAAG 4172 CUUUAGAAGAAACGCUUUA 4173AAAGCGUUUCUUCUAAAGG 4174 CCUUUAGAAGAAACGCUUU 4175 AAGCGUUUCUUCUAAAGGG4176 CCCUUUAGAAGAAACGCUU 4177 AAAGCAUGAUUUCCUGCCC 4178GGGCAGGAAAUCAUGCUUU 4179 AAGCAUGAUUUCCUGCCCU 4180 AGGGCAGGAAAUCAUGCUU4181 AGCAUGAUUUCCUGCCCUA 4182 UAGGGCAGGAAAUCAUGCU 4183GCAUGAUUUCCUGCCCUAA 4184 UUAGGGCAGGAAAUCAUGC 4185 CAUGAUUUCCUGCCCUAAG4186 CUUAGGGCAGGAAAUCAUG 4187 AUGAUUUCCUGCCCUAAGU 4188ACUUAGGGCAGGAAAUCAU 4189 UGAUUUCCUGCCCUAAGUC 4190 GACUUAGGGCAGGAAAUCA4191 GAUUUCCUGCCCUAAGUCC 4192 GGACUUAGGGCAGGAAAUC 4193AUUUCCUGCCCUAAGUCCU 4194 AGGACUUAGGGCAGGAAAU 4195 UUUCCUGCCCUAAGUCCUG4196 CAGGACUUAGGGCAGGAAA 4197 UUCCUGCCCUAAGUCCUGU 4198ACAGGACUUAGGGCAGGAA 4199 UCCUGCCCUAAGUCCUGUG 4200 CACAGGACUUAGGGCAGGA4201 AGAAGAUGUCAGGGACUAG 4202 CUAGUCCCUGACAUCUUCU 4203GAAGAUGUCAGGGACUAGG 4204 CCUAGUCCCUGACAUCUUC 4205 AAGAUGUCAGGGACUAGGG4206 CCCUAGUCCCUGACAUCUU 4207 AGAUGUCAGGGACUAGGGA 4208UCCCUAGUCCCUGACAUCU 4209 GUCAGGGACUAGGGAGGGA 4210 UCCCUCCCUAGUCCCUGAC4211 UACUUAGCCUCUCCCAAGA 4212 UCUUGGGAGAGGCUAAGUA 4213AGGAGGAAGCAGAUAGAUG 4214 CAUCUAUCUGCUUCCUCCU 4215 GGAGGAAGCAGAUAGAUGG4216 CCAUCUAUCUGCUUCCUCC 4217 GAGGAAGCAGAUAGAUGGU 4218ACCAUCUAUCUGCUUCCUC 4219 AGGAAGCAGAUAGAUGGUC 4220 GACCAUCUAUCUGCUUCCU4221 GGAAGCAGAUAGAUGGUCC 4222 GGACCAUCUAUCUGCUUCC 4223GAAGCAGAUAGAUGGUCCA 4224 UGGACCAUCUAUCUGCUUC 4225 UAGAUGGUCCAGCAGGCUU4226 AAGCCUGCUGGACCAUCUA 4227 AGAUGGUCCAGCAGGCUUG 4228CAAGCCUGCUGGACCAUCU 4229 GAUGGUCCAGCAGGCUUGA 4230 UCAAGCCUGCUGGACCAUC4231 AUGGUCCAGCAGGCUUGAA 4232 UUCAAGCCUGCUGGACCAU 4233UGGUCCAGCAGGCUUGAAG 4234 CUUCAAGCCUGCUGGACCA 4235 GGUCCAGCAGGCUUGAAGC4236 GCUUCAAGCCUGCUGGACC 4237 GUCCAGCAGGCUUGAAGCA 4238UGCUUCAAGCCUGCUGGAC 4239 UCCAGCAGGCUUGAAGCAG 4240 CUGCUUCAAGCCUGCUGGA4241 CCCAGGGUAAGGGCUGUUG 4242 CAACAGCCCUUACCCUGGG 4243GGGUAAGGGCUGUUGAGGU 4244 ACCUCAACAGCCCUUACCC 4245 GGUAAGGGCUGUUGAGGUA4246 UACCUCAACAGCCCUUACC 4247 GUAAGGGCUGUUGAGGUAC 4248GUACCUCAACAGCCCUUAC 4249 UAAGGGCUGUUGAGGUACC 4250 GGUACCUCAACAGCCCUUA4251 AAGGGCUGUUGAGGUACCU 4252 AGGUACCUCAACAGCCCUU 4253AGGGCUGUUGAGGUACCUU 4254 AAGGUACCUCAACAGCCCU 4255 GGGCUGUUGAGGUACCUUA4256 UAAGGUACCUCAACAGCCC 4257 GGCUGUUGAGGUACCUUAA 4258UUAAGGUACCUCAACAGCC 4259 GCUGUUGAGGUACCUUAAG 4260 CUUAAGGUACCUCAACAGC4261 CUGUUGAGGUACCUUAAGG 4262 CCUUAAGGUACCUCAACAG 4263UGUUGAGGUACCUUAAGGG 4264 CCCUUAAGGUACCUCAACA 4265 UAAGGGAAGGUCAAGAGGG4266 CCCUCUUGACCUUCCCUUA 4267 AAGGGAAGGUCAAGAGGGA 4268UCCCUCUUGACCUUCCCUU 4269 CGCUGAGGGAGGAUGCUUA 4270 UAAGCAUCCUCCCUCAGCG4271 UGAGGGAGGAUGCUUAGGG 4272 CCCUAAGCAUCCUCCCUCA 4273GGCACUAAGCCUAAGAAGU 4274 ACUUCUUAGGCUUAGUGCC 4275 GCACUAAGCCUAAGAAGUU4276 AACUUCUUAGGCUUAGUGC 4277 CACUAAGCCUAAGAAGUUC 4278GAACUUCUUAGGCUUAGUG 4279 ACUAAGCCUAAGAAGUUCC 4280 GGAACUUCUUAGGCUUAGU4281 AGAUCGAGUCUCGCUCUGU 4282 ACAGAGCGAGACUCGAUCU 4283GAUCGAGUCUCGCUCUGUC 4284 GACAGAGCGAGACUCGAUC 4285 AUCGAGUCUCGCUCUGUCA4286 UGACAGAGCGAGACUCGAU 4287 AGUCUCGCUCUGUCACCAG 4288CUGGUGACAGAGCGAGACU 4289 GUCUCGCUCUGUCACCAGG 4290 CCUGGUGACAGAGCGAGAC4291 UCUCGCUCUGUCACCAGGC 4292 GCCUGGUGACAGAGCGAGA 4293CUCGCUCUGUCACCAGGCU 4294 AGCCUGGUGACAGAGCGAG 4295 GUCACCAGGCUGGAGUGCA4296 UGCACUCCAGCCUGGUGAC 4297 GGCUCACUGCAACCUCCGU 4298ACGGAGGUUGCAGUGAGCC 4299 GCUCACUGCAACCUCCGUC 4300 GACGGAGGUUGCAGUGAGC4301 UCCGUCUCCUGGGUUCAAG 4302 CUUGAACCCAGGAGACGGA 4303CCGUCUCCUGGGUUCAAGU 4304 ACUUGAACCCAGGAGACGG 4305 CGUCUCCUGGGUUCAAGUG4306 CACUUGAACCCAGGAGACG 4307 GUCUCCUGGGUUCAAGUGA 4308UCACUUGAACCCAGGAGAC 4309 UGGGUUCAAGUGAUUCUUC 4310 GAAGAAUCACUUGAACCCA4311 GGGUUCAAGUGAUUCUUCU 4312 AGAAGAAUCACUUGAACCC 4313GGUUCAAGUGAUUCUUCUG 4314 CAGAAGAAUCACUUGAACC 4315 GUUCAAGUGAUUCUUCUGC4316 GCAGAAGAAUCACUUGAAC 4317 UUCAAGUGAUUCUUCUGCC 4318GGCAGAAGAAUCACUUGAA 4319 UCAAGUGAUUCUUCUGCCU 4320 AGGCAGAAGAAUCACUUGA4321 CGAGCAGCUGGGAUUACAG 4322 CUGUAAUCCCAGCUGCUCG 4323CAGCUGGGAUUACAGGCGC 4324 GCGCCUGUAAUCCCAGCUG 4325 ACAUGUUGGCCAGGAUGGU4326 ACCAUCCUGGCCAACAUGU 4327 CAUGUUGGCCAGGAUGGUC 4328GACCAUCCUGGCCAACAUG 4329 AUGUUGGCCAGGAUGGUCU 4330 AGACCAUCCUGGCCAACAU4331 UGUUGGCCAGGAUGGUCUC 4332 GAGACCAUCCUGGCCAACA 4333GUUGGCCAGGAUGGUCUCA 4334 UGAGACCAUCCUGGCCAAC 4335 UUGGCCAGGAUGGUCUCAA4336 UUGAGACCAUCCUGGCCAA 4337 UGGCCAGGAUGGUCUCAAU 4338AUUGAGACCAUCCUGGCCA 4339 GGCCAGGAUGGUCUCAAUC 4340 GAUUGAGACCAUCCUGGCC4341 GCCAGGAUGGUCUCAAUCU 4342 AGAUUGAGACCAUCCUGGC 4343CCAGGAUGGUCUCAAUCUC 4344 GAGAUUGAGACCAUCCUGG 4345 CAGGAUGGUCUCAAUCUCU4346 AGAGAUUGAGACCAUCCUG 4347 AGGAUGGUCUCAAUCUCUU 4348AAGAGAUUGAGACCAUCCU 4349 AUUAUAGGCGUGAGCCACC 4350 GGUGGCUCACGCCUAUAAU4351 UUAUAGGCGUGAGCCACCG 4352 CGGUGGCUCACGCCUAUAA 4353UAUAGGCGUGAGCCACCGC 4354 GCGGUGGCUCACGCCUAUA 4355 GCGCCUGGCUUAUACUUUC4356 GAAAGUAUAAGCCAGGCGC 4357 CGCCUGGCUUAUACUUUCU 4358AGAAAGUAUAAGCCAGGCG 4359 CCUGGCUUAUACUUUCUUA 4360 UAAGAAAGUAUAAGCCAGG4361 CUGGCUUAUACUUUCUUAA 4362 UUAAGAAAGUAUAAGCCAG 4363CAAAUGUGAGUCAUAAAGA 4364 UCUUUAUGACUCACAUUUG 4365 AAUGUGAGUCAUAAAGAAG4366 CUUCUUUAUGACUCACAUU 4367 UGAGUCAUAAAGAAGGGUU 4368AACCCUUCUUUAUGACUCA 4369 AGUCAUAAAGAAGGGUUAG 4370 CUAACCCUUCUUUAUGACU4371 GUCAUAAAGAAGGGUUAGG 4372 CCUAACCCUUCUUUAUGAC 4373UCAUAAAGAAGGGUUAGGG 4374 CCCUAACCCUUCUUUAUGA 4375 CAUAAAGAAGGGUUAGGGU4376 ACCCUAACCCUUCUUUAUG 4377 AAGAAGGGUUAGGGUGAUG 4378CAUCACCCUAACCCUUCUU 4379 AGAAGGGUUAGGGUGAUGG 4380 CCAUCACCCUAACCCUUCU4381 GAAGGGUUAGGGUGAUGGU 4382 ACCAUCACCCUAACCCUUC 4383AAGGGUUAGGGUGAUGGUC 4384 GACCAUCACCCUAACCCUU 4385 AGGGUUAGGGUGAUGGUCC4386 GGACCAUCACCCUAACCCU 4387 GGGUUAGGGUGAUGGUCCA 4388UGGACCAUCACCCUAACCC 4389 GGGUGAUGGUCCAGAGCAA 4390 UUGCUCUGGACCAUCACCC4391 GGUGAUGGUCCAGAGCAAC 4392 GUUGCUCUGGACCAUCACC 4393ACAGUUCUUCAAGUGUACU 4394 AGUACACUUGAAGAACUGU 4395 CAGUUCUUCAAGUGUACUC4396 GAGUACACUUGAAGAACUG 4397 AGUUCUUCAAGUGUACUCU 4398AGAGUACACUUGAAGAACU 4399 CAAGUGUACUCUGUAGGCU 4400 AGCCUACAGAGUACACUUG4401 AAGUGUACUCUGUAGGCUU 4402 AAGCCUACAGAGUACACUU 4403GUGUACUCUGUAGGCUUCU 4404 AGAAGCCUACAGAGUACAC 4405 UGUACUCUGUAGGCUUCUG4406 CAGAAGCCUACAGAGUACA 4407 GUACUCUGUAGGCUUCUGG 4408CCAGAAGCCUACAGAGUAC 4409 UACUCUGUAGGCUUCUGGG 4410 CCCAGAAGCCUACAGAGUA4411 GUAGGCUUCUGGGAGGUCC 4412 GGACCUCCCAGAAGCCUAC 4413UAGGCUUCUGGGAGGUCCC 4414 GGGACCUCCCAGAAGCCUA 4415 AGGCUUCUGGGAGGUCCCU4416 AGGGACCUCCCAGAAGCCU 4417 GGCUUCUGGGAGGUCCCUU 4418AAGGGACCUCCCAGAAGCC 4419 GCUUCUGGGAGGUCCCUUU 4420 AAAGGGACCUCCCAGAAGC4421 CUUCUGGGAGGUCCCUUUU 4422 AAAAGGGACCUCCCAGAAG 4423UUCUGGGAGGUCCCUUUUC 4424 GAAAAGGGACCUCCCAGAA 4425 UCUGGGAGGUCCCUUUUCA4426 UGAAAAGGGACCUCCCAGA 4427 CAUGUUAUUUGCCUUUUGA 4428UCAAAAGGCAAAUAACAUG 4429 AUUUGCCUUUUGAAUUCUC 4430 GAGAAUUCAAAAGGCAAAU4431 UUUGCCUUUUGAAUUCUCA 4432 UGAGAAUUCAAAAGGCAAA 4433UUGCCUUUUGAAUUCUCAU 4434 AUGAGAAUUCAAAAGGCAA 4435 UGCCUUUUGAAUUCUCAUU4436 AAUGAGAAUUCAAAAGGCA 4437 GCCUUUUGAAUUCUCAUUA 4438UAAUGAGAAUUCAAAAGGC 4439 AUUGUAUUGUGGAGUUUUC 4440 GAAAACUCCACAAUACAAU4441 UUGUAUUGUGGAGUUUUCC 4442 GGAAAACUCCACAAUACAA 4443AGUUUUCCAGAGGCCGUGU 4444 ACACGGCCUCUGGAAAACU 4445 GUUUUCCAGAGGCCGUGUG4446 CACACGGCCUCUGGAAAAC 4447 UUUUCCAGAGGCCGUGUGA 4448UCACACGGCCUCUGGAAAA 4449 UUUCCAGAGGCCGUGUGAC 4450 GUCACACGGCCUCUGGAAA4451 UUCCAGAGGCCGUGUGACA 4452 UGUCACACGGCCUCUGGAA 4453UCCAGAGGCCGUGUGACAU 4454 AUGUCACACGGCCUCUGGA 4455 CCAGAGGCCGUGUGACAUG4456 CAUGUCACACGGCCUCUGG 4457 CAGAGGCCGUGUGACAUGU 4458ACAUGUCACACGGCCUCUG 4459 AGAGGCCGUGUGACAUGUG 4460 CACAUGUCACACGGCCUCU4461 GCCGUGUGACAUGUGAUUA 4462 UAAUCACAUGUCACACGGC 4463CCGUGUGACAUGUGAUUAC 4464 GUAAUCACAUGUCACACGG 4465 CGUGUGACAUGUGAUUACA4466 UGUAAUCACAUGUCACACG 4467 GAUUACAUCAUCUUUCUGA 4468UCAGAAAGAUGAUGUAAUC 4469 AUUACAUCAUCUUUCUGAC 4470 GUCAGAAAGAUGAUGUAAU4471 UUACAUCAUCUUUCUGACA 4472 UGUCAGAAAGAUGAUGUAA 4473UACAUCAUCUUUCUGACAU 4474 AUGUCAGAAAGAUGAUGUA 4475 AUCUUUCUGACAUCAUUGU4476 ACAAUGAUGUCAGAAAGAU 4477 AUUGUUAAUGGAAUGUGUG 4478CACACAUUCCAUUAACAAU 4479 GAAUGUGUGCUUGUAUGGU 4480 ACCAUACAAGCACACAUUC4481 AAUGUGUGCUUGUAUGGUC 4482 GACCAUACAAGCACACAUU 4483AUGUGUGCUUGUAUGGUCU 4484 AGACCAUACAAGCACACAU 4485 UGUGUGCUUGUAUGGUCUU4486 AAGACCAUACAAGCACACA 4487 GUGUGCUUGUAUGGUCUUG 4488CAAGACCAUACAAGCACAC 4489 UGUGCUUGUAUGGUCUUGU 4490 ACAAGACCAUACAAGCACA4491 GUGCUUGUAUGGUCUUGUG 4492 CACAAGACCAUACAAGCAC 4493UGCUUGUAUGGUCUUGUGU 4494 ACACAAGACCAUACAAGCA 4495 GCUUGUAUGGUCUUGUGUU4496 AACACAAGACCAUACAAGC 4497 CUUGUAUGGUCUUGUGUUA 4498UAACACAAGACCAUACAAG 4499 UAUGGUCUUGUGUUACAGU 4500 ACUGUAACACAAGACCAUA4501 AUGGUCUUGUGUUACAGUC 4502 GACUGUAACACAAGACCAU 4503AGUCUCGCUCUGUCGCCCA 4504 UGGGCGACAGAGCGAGACU 4505 CAAUCUCGGCUCACUGCAA4506 UUGCAGUGAGCCGAGAUUG 4507 AAUCUCGGCUCACUGCAAC 4508GUUGCAGUGAGCCGAGAUU 4509 AUCUCGGCUCACUGCAACC 4510 GGUUGCAGUGAGCCGAGAU4511 UCUCGGCUCACUGCAACCU 4512 AGGUUGCAGUGAGCCGAGA 4513CUCACUGCAACCUCCACCU 4514 AGGUGGAGGUUGCAGUGAG 4515 UCACUGCAACCUCCACCUC4516 GAGGUGGAGGUUGCAGUGA 4517 CACUGCAACCUCCACCUCC 4518GGAGGUGGAGGUUGCAGUG 4519 ACUGCAACCUCCACCUCCC 4520 GGGAGGUGGAGGUUGCAGU4521 AGCCUCCUGAGUAGCUGGG 4522 CCCAGCUACUCAGGAGGCU 4523GCCUCCUGAGUAGCUGGGA 4524 UCCCAGCUACUCAGGAGGC 4525 CCUCCUGAGUAGCUGGGAC4526 GUCCCAGCUACUCAGGAGG 4527 CUCCUGAGUAGCUGGGACU 4528AGUCCCAGCUACUCAGGAG 4529 UCCUGAGUAGCUGGGACUA 4530 UAGUCCCAGCUACUCAGGA4531 UAGCUGGGACUACAGGCCU 4532 AGGCCUGUAGUCCCAGCUA 4533AGCUGGGACUACAGGCCUG 4534 CAGGCCUGUAGUCCCAGCU 4535 GCCACCAUGCCCAGCUAUU4536 AAUAGCUGGGCAUGGUGGC 4537 CCACCAUGCCCAGCUAUUU 4538AAAUAGCUGGGCAUGGUGG 4539 CACCAUGCCCAGCUAUUUU 4540 AAAAUAGCUGGGCAUGGUG4541 GGGUUUCACCAUGUUGGCC 4542 GGCCAACAUGGUGAAACCC 4543GGUUUCACCAUGUUGGCCA 4544 UGGCCAACAUGGUGAAACC 4545 GUUUCACCAUGUUGGCCAG4546 CUGGCCAACAUGGUGAAAC 4547 CACCAUGUUGGCCAGGCUG 4548CAGCCUGGCCAACAUGGUG 4549 ACCAUGUUGGCCAGGCUGG 4550 CCAGCCUGGCCAACAUGGU4551 CCAUGUUGGCCAGGCUGGU 4552 ACCAGCCUGGCCAACAUGG 4553CAUGUUGGCCAGGCUGGUC 4554 GACCAGCCUGGCCAACAUG 4555 AUGUUGGCCAGGCUGGUCU4556 AGACCAGCCUGGCCAACAU 4557 UGUUGGCCAGGCUGGUCUC 4558GAGACCAGCCUGGCCAACA 4559 CUUGAGGUGAUCCGCCUGC 4560 GCAGGCGGAUCACCUCAAG4561 UUGAGGUGAUCCGCCUGCC 4562 GGCAGGCGGAUCACCUCAA 4563UGAGGUGAUCCGCCUGCCU 4564 AGGCAGGCGGAUCACCUCA 4565 CCAAAGUGCUGGGAUUACA4566 UGUAAUCCCAGCACUUUGG 4567 CAAAGUGCUGGGAUUACAG 4568CUGUAAUCCCAGCACUUUG 4569 GUGCUGGGAUUACAGGUCU 4570 AGACCUGUAAUCCCAGCAC4571 UGCUGGGAUUACAGGUCUG 4572 CAGACCUGUAAUCCCAGCA 4573GCUGGGAUUACAGGUCUGA 4574 UCAGACCUGUAAUCCCAGC 4575 CUGGGAUUACAGGUCUGAG4576 CUCAGACCUGUAAUCCCAG 4577 GGUCUGAGCCACUGUGCCU 4578AGGCACAGUGGCUCAGACC 4579 GUCUGAGCCACUGUGCCUA 4580 UAGGCACAGUGGCUCAGAC4581 UCUGAGCCACUGUGCCUAA 4582 UUAGGCACAGUGGCUCAGA 4583CUGAGCCACUGUGCCUAAC 4584 GUUAGGCACAGUGGCUCAG 4585 UGAGCCACUGUGCCUAACC4586 GGUUAGGCACAGUGGCUCA 4587 CACUGUGCCUAACCUAAUG 4588CAUUAGGUUAGGCACAGUG 4589 ACUGUGCCUAACCUAAUGA 4590 UCAUUAGGUUAGGCACAGU4591 CUGUGCCUAACCUAAUGAC 4592 GUCAUUAGGUUAGGCACAG 4593UGUGCCUAACCUAAUGACU 4594 AGUCAUUAGGUUAGGCACA 4595 GUGCCUAACCUAAUGACUU4596 AAGUCAUUAGGUUAGGCAC 4597 UGCCUAACCUAAUGACUUU 4598AAAGUCAUUAGGUUAGGCA 4599 GCCUAACCUAAUGACUUUU 4600 AAAAGUCAUUAGGUUAGGC4601 CCUAACCUAAUGACUUUUA 4602 UAAAAGUCAUUAGGUUAGG 4603ACCUAAUGACUUUUAAGAG 4604 CUCUUAAAAGUCAUUAGGU 4605 CUUUUAAGAGUAUAGAGGA4606 UCCUCUAUACUCUUAAAAG 4607 GACUCACUGGUCUAUAGAA 4608UUCUAUAGACCAGUGAGUC 4609 AAAGUAAGGUGUUCUAAGA 4610 UCUUAGAACACCUUACUUU4611 GAGCUCUUCUUGCUGGGCA 4612 UGCCCAGCAAGAAGAGCUC 4613AGCUCUUCUUGCUGGGCAC 4614 GUGCCCAGCAAGAAGAGCU 4615 GCUCUUCUUGCUGGGCACC4616 GGUGCCCAGCAAGAAGAGC 4617 CUCUUCUUGCUGGGCACCG 4618CGGUGCCCAGCAAGAAGAG 4619 UCUUCUUGCUGGGCACCGG 4620 CCGGUGCCCAGCAAGAAGA4621 CUUCUUGCUGGGCACCGGU 4622 ACCGGUGCCCAGCAAGAAG 4623UUCUUGCUGGGCACCGGUG 4624 CACCGGUGCCCAGCAAGAA 4625 CCCAGGAGUUCGAGGCUAU4626 AUAGCCUCGAACUCCUGGG 4627 CCAGGAGUUCGAGGCUAUG 4628CAUAGCCUCGAACUCCUGG 4629 AGUUCGAGGCUAUGAUCAC 4630 GUGAUCAUAGCCUCGAACU4631 GUUCGAGGCUAUGAUCACA 4632 UGUGAUCAUAGCCUCGAAC 4633UUCGAGGCUAUGAUCACAC 4634 GUGUGAUCAUAGCCUCGAA 4635 UCGAGGCUAUGAUCACACU4636 AGUGUGAUCAUAGCCUCGA 4637 CGAGGCUAUGAUCACACUU 4638AAGUGUGAUCAUAGCCUCG 4639 GAGGCUAUGAUCACACUUG 4640 CAAGUGUGAUCAUAGCCUC4641 UGCACUCCAGCCUGGGCAA 4642 UUGCCCAGGCUGGAGUGCA 4643GCACUCCAGCCUGGGCAAA 4644 UUUGCCCAGGCUGGAGUGC 4645 CACUCCAGCCUGGGCAAAU4646 AUUUGCCCAGGCUGGAGUG 4647 ACUCCAGCCUGGGCAAAUA 4648UAUUUGCCCAGGCUGGAGU 4649 UACAUAAAUAGCUCCUCUG 4650 CAGAGGAGCUAUUUAUGUA4651 ACAUAAAUAGCUCCUCUGG 4652 CCAGAGGAGCUAUUUAUGU 4653CAUAAAUAGCUCCUCUGGA 4654 UCCAGAGGAGCUAUUUAUG 4655 AUAAAUAGCUCCUCUGGAA4656 UUCCAGAGGAGCUAUUUAU 4657 AAAUAGCUCCUCUGGAAGA 4658UCUUCCAGAGGAGCUAUUU 4659 AGGCUGGGACAGGAGCAUG 4660 CAUGCUCCUGUCCCAGCCU4661 GGCUGGGACAGGAGCAUGU 4662 ACAUGCUCCUGUCCCAGCC 4663GCUGGGACAGGAGCAUGUG 4664 CACAUGCUCCUGUCCCAGC 4665 UGGGACAGGAGCAUGUGUG4666 CACACAUGCUCCUGUCCCA 4667 GGGACAGGAGCAUGUGUGG 4668CCACACAUGCUCCUGUCCC 4669 GGACAGGAGCAUGUGUGGG 4670 CCCACACAUGCUCCUGUCC4671 UUUUCAGUGCCCAUUAGUC 4672 GACUAAUGGGCACUGAAAA 4673UUUCAGUGCCCAUUAGUCU 4674 AGACUAAUGGGCACUGAAA 4675 UUCAGUGCCCAUUAGUCUG4676 CAGACUAAUGGGCACUGAA 4677 CAGUGCCCAUUAGUCUGGU 4678ACCAGACUAAUGGGCACUG 4679 AGUGCCCAUUAGUCUGGUC 4680 GACCAGACUAAUGGGCACU4681 GUGCCCAUUAGUCUGGUCU 4682 AGACCAGACUAAUGGGCAC 4683UGCCCAUUAGUCUGGUCUG 4684 CAGACCAGACUAAUGGGCA 4685 GCCCAUUAGUCUGGUCUGA4686 UCAGACCAGACUAAUGGGC 4687 GUCUGGUCUGACUGAGCUG 4688CAGCUCAGUCAGACCAGAC 4689 UCUGGUCUGACUGAGCUGG 4690 CCAGCUCAGUCAGACCAGA4691 CUGGUCUGACUGAGCUGGG 4692 CCCAGCUCAGUCAGACCAG 4693UGGUCUGACUGAGCUGGGU 4694 ACCCAGCUCAGUCAGACCA 4695 GGUCUGACUGAGCUGGGUC4696 GACCCAGCUCAGUCAGACC 4697 GUCUGACUGAGCUGGGUCU 4698AGACCCAGCUCAGUCAGAC 4699 UCUGACUGAGCUGGGUCUC 4700 GAGACCCAGCUCAGUCAGA4701 CUGACUGAGCUGGGUCUCU 4702 AGAGACCCAGCUCAGUCAG 4703UGACUGAGCUGGGUCUCUG 4704 CAGAGACCCAGCUCAGUCA 4705 GACUGAGCUGGGUCUCUGA4706 UCAGAGACCCAGCUCAGUC 4707 ACUGAGCUGGGUCUCUGAC 4708GUCAGAGACCCAGCUCAGU 4709 GGGAUAACUAGCCUGGGUC 4710 GACCCAGGCUAGUUAUCCC4711 GGAUAACUAGCCUGGGUCA 4712 UGACCCAGGCUAGUUAUCC 4713GAUAACUAGCCUGGGUCAA 4714 UUGACCCAGGCUAGUUAUC 4715 AUAACUAGCCUGGGUCAAA4716 UUUGACCCAGGCUAGUUAU 4717 UAACUAGCCUGGGUCAAAG 4718CUUUGACCCAGGCUAGUUA 4719 AACUAGCCUGGGUCAAAGU 4720 ACUUUGACCCAGGCUAGUU4721 ACUAGCCUGGGUCAAAGUC 4722 GACUUUGACCCAGGCUAGU 4723CUAGCCUGGGUCAAAGUCC 4724 GGACUUUGACCCAGGCUAG 4725 UAGCCUGGGUCAAAGUCCC4726 GGGACUUUGACCCAGGCUA 4727 GGUCAAAGUCCCAGAUCUC 4728GAGAUCUGGGACUUUGACC 4729 GUCAAAGUCCCAGAUCUCC 4730 GGAGAUCUGGGACUUUGAC4731 UCAAAGUCCCAGAUCUCCC 4732 GGGAGAUCUGGGACUUUGA 4733CCUACCUUCACCUUUUCUU 4734 AAGAAAAGGUGAAGGUAGG 4735 CCUUCACCUUUUCUUUUCC4736 GGAAAAGAAAAGGUGAAGG 4737 AACCCACUGACCUUCCACA 4738UGUGGAAGGUCAGUGGGUU 4739 ACCCACUGACCUUCCACAC 4740 GUGUGGAAGGUCAGUGGGU4741 ACUGACCUUCCACACCCAA 4742 UUGGGUGUGGAAGGUCAGU 4743CUGACCUUCCACACCCAAG 4744 CUUGGGUGUGGAAGGUCAG 4745 GGGUGGUUCUUGGAAGCAG4746 CUGCUUCCAAGAACCACCC 4747 GGUGGUUCUUGGAAGCAGA 4748UCUGCUUCCAAGAACCACC 4749 GUGGUUCUUGGAAGCAGAG 4750 CUCUGCUUCCAAGAACCAC4751 UGGUUCUUGGAAGCAGAGC 4752 GCUCUGCUUCCAAGAACCA 4753GGUUCUUGGAAGCAGAGCU 4754 AGCUCUGCUUCCAAGAACC 4755 GUUCUUGGAAGCAGAGCUA4756 UAGCUCUGCUUCCAAGAAC 4757 UUCUUGGAAGCAGAGCUAG 4758CUAGCUCUGCUUCCAAGAA 4759 CUUGGAAGCAGAGCUAGGA 4760 UCCUAGCUCUGCUUCCAAG4761 UGGAAGCAGAGCUAGGAUG 4762 CAUCCUAGCUCUGCUUCCA 4763GGAAGCAGAGCUAGGAUGU 4764 ACAUCCUAGCUCUGCUUCC 4765 AGCUAGGAUGUGGGAGGUC4766 GACCUCCCACAUCCUAGCU 4767 GCUAGGAUGUGGGAGGUCU 4768AGACCUCCCACAUCCUAGC 4769 CUAGGAUGUGGGAGGUCUG 4770 CAGACCUCCCACAUCCUAG4771 UAGGAUGUGGGAGGUCUGC 4772 GCAGACCUCCCACAUCCUA 4773AGGAUGUGGGAGGUCUGCC 4774 GGCAGACCUCCCACAUCCU 4775 GGAUGUGGGAGGUCUGCCU4776 AGGCAGACCUCCCACAUCC 4777 GAUGUGGGAGGUCUGCCUG 4778CAGGCAGACCUCCCACAUC 4779 AUGUGGGAGGUCUGCCUGU 4780 ACAGGCAGACCUCCCACAU4781 UUUCCUUGUCAUGCUUCCU 4782 AGGAAGCAUGACAAGGAAA 4783UUCCUUGUCAUGCUUCCUC 4784 GAGGAAGCAUGACAAGGAA 4785 UGUCAUGCUUCCUCCUCUU4786 AAGAGGAGGAAGCAUGACA 4787 UCAUGCUUCCUCCUCUUUC 4788GAAAGAGGAGGAAGCAUGA 4789 CUUCCUCCUCUUUCUCAUA 4790 UAUGAGAAAGAGGAGGAAG4791 UCCUCCUCUUUCUCAUAAA 4792 UUUAUGAGAAAGAGGAGGA 4793CCUCCUCUUUCUCAUAAAA 4794 UUUUAUGAGAAAGAGGAGG 4795 UCACGAUGGCAAUGCAAAU4796 AUUUGCAUUGCCAUCGUGA 4797 CACGAUGGCAAUGCAAAUC 4798GAUUUGCAUUGCCAUCGUG 4799 ACGAUGGCAAUGCAAAUCU 4800 AGAUUUGCAUUGCCAUCGU4801 CGAUGGCAAUGCAAAUCUA 4802 UAGAUUUGCAUUGCCAUCG 4803GAUGGCAAUGCAAAUCUAA 4804 UUAGAUUUGCAUUGCCAUC 4805 UGGCAAUGCAAAUCUAAAG4806 CUUUAGAUUUGCAUUGCCA 4807 GGCAAUGCAAAUCUAAAGA 4808UCUUUAGAUUUGCAUUGCC 4809 AUGCAAAUCUAAAGAGGCA 4810 UGCCUCUUUAGAUUUGCAU4811 GCAAAUCUAAAGAGGCAGG 4812 CCUGCCUCUUUAGAUUUGC 4813CAAAUCUAAAGAGGCAGGG 4814 CCCUGCCUCUUUAGAUUUG 4815 AAAUCUAAAGAGGCAGGGC4816 GCCCUGCCUCUUUAGAUUU 4817 ACUUCCCUGUCAGGCAGUA 4818UACUGCCUGACAGGGAAGU 4819 CUUCCCUGUCAGGCAGUAC 4820 GUACUGCCUGACAGGGAAG4821 UUCCCUGUCAGGCAGUACC 4822 GGUACUGCCUGACAGGGAA 4823UCCCUGUCAGGCAGUACCG 4824 CGGUACUGCCUGACAGGGA 4825 CCUGUCAGGCAGUACCGCU4826 AGCGGUACUGCCUGACAGG 4827 CUGUCAGGCAGUACCGCUG 4828CAGCGGUACUGCCUGACAG 4829 UGUCAGGCAGUACCGCUGG 4830 CCAGCGGUACUGCCUGACA4831 AGGCAGUACCGCUGGGCAU 4832 AUGCCCAGCGGUACUGCCU 4833GGCAGUACCGCUGGGCAUA 4834 UAUGCCCAGCGGUACUGCC 4835 GCAGUACCGCUGGGCAUAG4836 CUAUGCCCAGCGGUACUGC 4837 UACCGCUGGGCAUAGCAAC 4838GUUGCUAUGCCCAGCGGUA 4839 ACCGCUGGGCAUAGCAACC 4840 GGUUGCUAUGCCCAGCGGU4841 CCGCUGGGCAUAGCAACCU 4842 AGGUUGCUAUGCCCAGCGG 4843CCUCUGCCUCUCCGUUUCU 4844 AGAAACGGAGAGGCAGAGG 4845 UGCCUCUCCGUUUCUCAGA4846 UCUGAGAAACGGAGAGGCA 4847 UCUCCGUUUCUCAGAGCUC 4848GAGCUCUGAGAAACGGAGA 4849 CUCCGUUUCUCAGAGCUCA 4850 UGAGCUCUGAGAAACGGAG4851 UCCGUUUCUCAGAGCUCAC 4852 GUGAGCUCUGAGAAACGGA 4853CCGUUUCUCAGAGCUCACA 4854 UGUGAGCUCUGAGAAACGG 4855 CGUUUCUCAGAGCUCACAU4856 AUGUGAGCUCUGAGAAACG 4857 UUUCUCAGAGCUCACAUAU 4858AUAUGUGAGCUCUGAGAAA 4859 AGAGCUCACAUAUCCACCU 4860 AGGUGGAUAUGUGAGCUCU4861 GAGCUCACAUAUCCACCUC 4862 GAGGUGGAUAUGUGAGCUC 4863AGCUCACAUAUCCACCUCC 4864 GGAGGUGGAUAUGUGAGCU 4865 CAUAUCCACCUCCUGGGCU4866 AGCCCAGGAGGUGGAUAUG 4867 AUAUCCACCUCCUGGGCUU 4868AAGCCCAGGAGGUGGAUAU 4869 UAUCCACCUCCUGGGCUUU 4870 AAAGCCCAGGAGGUGGAUA4871 AUCCACCUCCUGGGCUUUU 4872 AAAAGCCCAGGAGGUGGAU 4873UCCACCUCCUGGGCUUUUA 4874 UAAAAGCCCAGGAGGUGGA 4875 CCACCUCCUGGGCUUUUAA4876 UUAAAAGCCCAGGAGGUGG 4877 UCCUGGGCUUUUAAGUGGG 4878CCCACUUAAAAGCCCAGGA 4879 CCUGGGCUUUUAAGUGGGC 4880 GCCCACUUAAAAGCCCAGG4881 CUGGGCUUUUAAGUGGGCU 4882 AGCCCACUUAAAAGCCCAG 4883UGGGCUUUUAAGUGGGCUU 4884 AAGCCCACUUAAAAGCCCA 4885 GGGCUUUUAAGUGGGCUUU4886 AAAGCCCACUUAAAAGCCC 4887 UUUUAAGUGGGCUUUAGUG 4888CACUAAAGCCCACUUAAAA 4889 UUUAAGUGGGCUUUAGUGA 4890 UCACUAAAGCCCACUUAAA4891 UUAAGUGGGCUUUAGUGAG 4892 CUCACUAAAGCCCACUUAA 4893UAAGUGGGCUUUAGUGAGG 4894 CCUCACUAAAGCCCACUUA 4895 AAGUGGGCUUUAGUGAGGG4896 CCCUCACUAAAGCCCACUU 4897 GGGCUCCUCCUUCAACUGG 4898CCAGUUGAAGGAGGAGCCC 4899 GGCUCCUCCUUCAACUGGG 4900 CCCAGUUGAAGGAGGAGCC4901 GCUCCUCCUUCAACUGGGC 4902 GCCCAGUUGAAGGAGGAGC 4903CAACUGGGCUCCUCCUUCA 4904 UGAAGGAGGAGCCCAGUUG 4905 AACUGGGCUCCUCCUUCAG4906 CUGAAGGAGGAGCCCAGUU 4907 UGGGCUCCUCCUUCAGUUC 4908GAACUGAAGGAGGAGCCCA 4909 GGGCUCCUCCUUCAGUUCC 4910 GGAACUGAAGGAGGAGCCC4911 CCCAGCUCUUCUGCUUCGA 4912 UCGAAGCAGAAGAGCUGGG 4913CCAGCUCUUCUGCUUCGAC 4914 GUCGAAGCAGAAGAGCUGG 4915 CAGCUCUUCUGCUUCGACU4916 AGUCGAAGCAGAAGAGCUG 4917 AGCUCUUCUGCUUCGACUC 4918GAGUCGAAGCAGAAGAGCU 4919 GCUCUUCUGCUUCGACUCC 4920 GGAGUCGAAGCAGAAGAGC4921 CUCUUCUGCUUCGACUCCG 4922 CGGAGUCGAAGCAGAAGAG 4923UCUUCUGCUUCGACUCCGA 4924 UCGGAGUCGAAGCAGAAGA 4925 CUUCUGCUUCGACUCCGAG4926 CUCGGAGUCGAAGCAGAAG 4927 UUCGACUCCGAGCGGGUGU 4928ACACCCGCUCGGAGUCGAA 4929 UCCGAGCGGGUGUCAUGUG 4930 CACAUGACACCCGCUCGGA4931 CCGAGCGGGUGUCAUGUGU 4932 ACACAUGACACCCGCUCGG 4933CGAGCGGGUGUCAUGUGUG 4934 CACACAUGACACCCGCUCG 4935 GAGCGGGUGUCAUGUGUGA4936 UCACACAUGACACCCGCUC 4937

The inhibitory nucleic acid molecules disclosed herein can comprise RNA,DNA, or both RNA and DNA. The inhibitory nucleic acid molecules can alsobe linked or fused to a heterologous nucleic acid sequence, such as in avector, or a heterologous label. For example, the inhibitory nucleicacid molecules disclosed herein can be within a vector or as anexogenous donor sequence comprising the inhibitory nucleic acid moleculeand a heterologous nucleic acid sequence. The inhibitory nucleic acidmolecules can also be linked or fused to a heterologous label. The labelcan be directly detectable (such as, for example, fluorophore) orindirectly detectable (such as, for example, hapten, enzyme, orfluorophore quencher). Such labels can be detectable by spectroscopic,photochemical, biochemical, immunochemical, or chemical means. Suchlabels include, for example, radiolabels, pigments, dyes, chromogens,spin labels, and fluorescent labels. The label can also be, for example,a chemiluminescent substance; a metal-containing substance; or anenzyme, where there occurs an enzyme-dependent secondary generation ofsignal. The term “label” can also refer to a “tag” or hapten that canbind selectively to a conjugated molecule such that the conjugatedmolecule, when added subsequently along with a substrate, is used togenerate a detectable signal. For example, biotin can be used as a tagalong with an avidin or streptavidin conjugate of horseradish peroxidate(HRP) to bind to the tag, and examined using a calorimetric substrate(such as, for example, tetramethylbenzidine (TMB)) or a fluorogenicsubstrate to detect the presence of HRP. Exemplary labels that can beused as tags to facilitate purification include, but are not limited to,myc, HA, FLAG or 3×FLAG, 6×His or polyhistidine,glutathione-S-transferase (GST), maltose binding protein, an epitopetag, or the Fc portion of immunoglobulin. Numerous labels include, forexample, particles, fluorophores, haptens, enzymes and theircalorimetric, fluorogenic and chemiluminescent substrates and otherlabels.

The disclosed inhibitory nucleic acid molecules can comprise, forexample, nucleotides or non-natural or modified nucleotides, such asnucleotide analogs or nucleotide substitutes. Such nucleotides include anucleotide that contains a modified base, sugar, or phosphate group, orthat incorporates a non-natural moiety in its structure. Examples ofnon-natural nucleotides include, but are not limited to,dideoxynucleotides, biotinylated, aminated, deaminated, alkylated,benzylated, and fluorophor-labeled nucleotides.

The inhibitory nucleic acid molecules disclosed herein can also compriseone or more nucleotide analogs or substitutions. A nucleotide analog isa nucleotide which contains a modification to either the base, sugar, orphosphate moieties. Modifications to the base moiety include, but arenot limited to, natural and synthetic modifications of A, C, G, and T/U,as well as different purine or pyrimidine bases such as, for example,pseudouridine, uracil-5-yl, hypoxanthin-9-yl (I), and2-aminoadenin-9-yl. Modified bases include, but are not limited to,5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine,hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives ofadenine and guanine, 2-propyl and other alkyl derivatives of adenine andguanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouraciland cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine andthymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino,8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines andguanines, 5-halo (such as, for example, 5-bromo), 5-trifluoromethyl andother 5-substituted uracils and cytosines, 7-methylguanine,7-methyladenine, 8-azaguanine, 8-azaadenine, 7-deazaguanine,7-deazaadenine, 3-deazaguanine, and 3-deazaadenine.

Nucleotide analogs can also include modifications of the sugar moiety.Modifications to the sugar moiety include, but are not limited to,natural modifications of the ribose and deoxy ribose as well assynthetic modifications. Sugar modifications include, but are notlimited to, the following modifications at the 2′ position: OH; F; O-,S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; orO-alkyl-O-alkyl, wherein the alkyl, alkenyl, and alkynyl may besubstituted or unsubstituted C₁₋₁₀alkyl or C₂₋₁₀alkenyl, andC₂₋₁₀alkynyl. Exemplary 2′ sugar modifications also include, but are notlimited to, —O[(CH₂)_(n)O]_(m)CH₃, —O(CH₂)_(n)OCH₃, —O(CH₂)_(n)NH₂,—O(CH₂)_(n)CH₃, —O(CH₂)_(n)—ONH₂, and —O(CH₂)_(n)ON[(CH₂)_(n)CH₃)]₂,where n and m, independently, are from 1 to about 10. Othermodifications at the 2′ position include, but are not limited to,C₁₋₁₀alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl orO-aralkyl, SH, SCH₃, OCN, Cl, Br, CN, CF₃, OCF₃, SOCH₃, SO₂CH₃, ONO₂,NO₂, N₃, NH₂, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino,polyalkylamino, substituted silyl, an RNA cleaving group, a reportergroup, an intercalator, a group for improving the pharmacokineticproperties of an oligonucleotide, or a group for improving thepharmacodynamic properties of an oligonucleotide, and other substituentshaving similar properties. Similar modifications may also be made atother positions on the sugar, particularly the 3′ position of the sugaron the 3′ terminal nucleotide or in 2′-5′ linked oligonucleotides andthe 5′ position of 5′ terminal nucleotide. Modified sugars can alsoinclude those that contain modifications at the bridging ring oxygen,such as CH₂ and S. Nucleotide sugar analogs can also have sugarmimetics, such as cyclobutyl moieties in place of the pentofuranosylsugar.

Nucleotide analogs can also be modified at the phosphate moiety.Modified phosphate moieties include, but are not limited to, those thatcan be modified so that the linkage between two nucleotides contains aphosphorothioate, chiral phosphorothioate, phosphorodithioate,phosphotriester, aminoalkylphosphotriester, methyl and other alkylphosphonates including 3′-alkylene phosphonate and chiral phosphonates,phosphinates, phosphoramidates including 3′-amino phosphoramidate andaminoalkylphosphoramidates, thionophosphoramidates,thionoalkylphosphonates, thionoalkylphosphotriesters, andboranophosphates. These phosphate or modified phosphate linkage betweentwo nucleotides can be through a 3′-5′ linkage or a 2′-5′ linkage, andthe linkage can contain inverted polarity such as 3′-5′ to 5′-3′ or2′-5′ to 5′-2′. Various salts, mixed salts, and free acid forms are alsoincluded. Nucleotide substitutes also include peptide nucleic acids(PNAs).

In some embodiments, the antisense nucleic acid molecules are gapmers,whereby the first one to seven nucleotides at the 5′ and 3′ ends eachhave 2′-methoxyethyl (2′-MOE) modifications. In some embodiments, thefirst five nucleotides at the 5′ and 3′ ends each have 2′-MOEmodifications. In some embodiments, the first one to seven nucleotidesat the 5′ and 3′ ends are RNA nucleotides. In some embodiments, thefirst five nucleotides at the 5′ and 3′ ends are RNA nucleotides. Insome embodiments, each of the backbone linkages between the nucleotidesis a phosphorothioate linkage.

In some embodiments, the siRNA molecules have termini modifications. Insome embodiments, the 5′ end of the antisense strand is phosphorylated.In some embodiments, 5′-phosphate analogs that cannot be hydrolyzed,such as 5′-(E)-vinyl-phosphonate are used.

In some embodiments, the siRNA molecules have backbone modifications. Insome embodiments, the modified phosphodiester groups that linkconsecutive ribose nucleosides have been shown to enhance the stabilityand in vivo bioavailability of siRNAs The non-ester groups (—OH, ═O) ofthe phosphodiester linkage can be replaced with sulfur, boron, oracetate to give phosphorothioate, boranophosphate, and phosphonoacetatelinkages. In addition, substituting the phosphodiester group with aphosphotriester can facilitate cellular uptake of siRNAs and retentionon serum components by eliminating their negative charge. In someembodiments, the siRNA molecules have sugar modifications. In someembodiments, the sugars are deprotonated (reaction catalyzed by exo- andendonucleases) whereby the 2′-hydroxyl can act as a nucleophile andattack the adjacent phosphorous in the phosphodiester bond. Suchalternatives include 2′-O-methyl, 2′-O-methoxyethyl, and 2′-fluoromodifications.

In some embodiments, the siRNA molecules have base modifications. Insome embodiments, the bases can be substituted with modified bases suchas pseudouridine, 5′-methylcytidine, N6-methyladenosine, inosine, andN7-methylguanosine.

In some embodiments, the siRNA molecules are conjugated to lipids.Lipids can be conjugated to the 5′ or 3′ termini of siRNA to improvetheir in vivo bioavailability by allowing them to associate with serumlipoproteins. Representative lipids include, but are not limited to,cholesterol and vitamin E, and fatty acids, such as palmitate andtocopherol.

In some embodiments, a representative siRNA has the following formula:

Sense:mN*mN*/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/*mN*/32FN/

Antisense:/52FN/*/i2FN/*mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN*N*N

wherein: “N” is the base; “2F” is a 2′-F modification; “m” is a2′-O-methyl modification, “I” is an internal base; and “*” is aphosphorothioate backbone linkage.

The present disclosure also provides vectors comprising any one or moreof the inhibitory nucleic acid molecules disclosed herein. In someembodiments, the vectors comprise any one or more of the inhibitorynucleic acid molecules disclosed herein and a heterologous nucleic acid.The vectors can be viral or nonviral vectors capable of transporting anucleic acid molecule. In some embodiments, the vector is a plasmid orcosmid (such as, for example, a circular double-stranded DNA into whichadditional DNA segments can be ligated). In some embodiments, the vectoris a viral vector, wherein additional DNA segments can be ligated intothe viral genome. Expression vectors include, but are not limited to,plasmids, cosmids, retroviruses, adenoviruses, adeno-associated viruses(AAV), plant viruses such as cauliflower mosaic virus and tobacco mosaicvirus, yeast artificial chromosomes (YACs), Epstein-Barr (EBV)-derivedepisomes, and other expression vectors known in the art.

The present disclosure also provides compositions comprising any one ormore of the inhibitory nucleic acid molecules disclosed herein. In someembodiments, the composition is a pharmaceutical composition. In someembodiments, the compositions comprise a carrier and/or excipient.Examples of carriers include, but are not limited to, poly(lactic acid)(PLA) microspheres, poly(D,L-lactic-coglycolic-acid) (PLGA)microspheres, liposomes, micelles, inverse micelles, lipid cochleates,and lipid microtubules. A carrier may comprise a buffered salt solutionsuch as PBS, HBSS, etc.

In some embodiments, the INHBE inhibitor comprises a nuclease agent thatinduces one or more nicks or double-strand breaks at a recognitionsequence(s) or a DNA-binding protein that binds to a recognitionsequence within an INHBE genomic nucleic acid molecule. The recognitionsequence can be located within a coding region of the INHBE gene, orwithin regulatory regions that influence the expression of the gene. Arecognition sequence of the DNA-binding protein or nuclease agent can belocated in an intron, an exon, a promoter, an enhancer, a regulatoryregion, or any non-protein coding region. The recognition sequence caninclude or be proximate to the start codon of the INHBE gene. Forexample, the recognition sequence can be located about 10, about 20,about 30, about 40, about 50, about 100, about 200, about 300, about400, about 500, or about 1,000 nucleotides from the start codon. Asanother example, two or more nuclease agents can be used, each targetinga nuclease recognition sequence including or proximate to the startcodon. As another example, two nuclease agents can be used, onetargeting a nuclease recognition sequence including or proximate to thestart codon, and one targeting a nuclease recognition sequence includingor proximate to the stop codon, wherein cleavage by the nuclease agentscan result in deletion of the coding region between the two nucleaserecognition sequences. Any nuclease agent that induces a nick ordouble-strand break into a desired recognition sequence can be used inthe methods and compositions disclosed herein. Any DNA-binding proteinthat binds to a desired recognition sequence can be used in the methodsand compositions disclosed herein.

Suitable nuclease agents and DNA-binding proteins for use hereininclude, but are not limited to, zinc finger protein or zinc fingernuclease (ZFN) pair, Transcription Activator-Like Effector (TALE)protein or Transcription Activator-Like Effector Nuclease (TALEN), orClustered Regularly Interspersed Short Palindromic Repeats(CRISPR)/CRISPR-associated (Cas) systems. The length of the recognitionsequence can vary, and includes, for example, recognition sequences thatare about 30-36 bp for a zinc finger protein or ZFN pair, about 15-18 bpfor each ZFN, about 36 bp for a TALE protein or TALEN, and about 20 bpfor a CRISPR/Cas guide RNA.

In some embodiments, CRISPR/Cas systems can be used to modify an INHBEgenomic nucleic acid molecule within a cell. The methods andcompositions disclosed herein can employ CRISPR-Cas systems by utilizingCRISPR complexes (comprising a guide RNA (gRNA) complexed with a Casprotein) for site-directed cleavage of INHBE nucleic acid molecules.

Cas proteins generally comprise at least one RNA recognition or bindingdomain that can interact with gRNAs. Cas proteins can also comprisenuclease domains (such as, for example, DNase or RNase domains), DNAbinding domains, helicase domains, protein-protein interaction domains,dimerization domains, and other domains. Suitable Cas proteins include,for example, a wild type Cas9 protein and a wild type Cpf1 protein (suchas, for example, FnCpf1). A Cas protein can have full cleavage activityto create a double-strand break in an INHBE genomic nucleic acidmolecule or it can be a nickase that creates a single-strand break in anINHBE genomic nucleic acid molecule. Additional examples of Cas proteinsinclude, but are not limited to, Cas1, Cas1B, Cast, Cas3, Cas4, Cas5,Cas5e (CasD), Cas6, Cas6e, Cas6f, Cas7, Cas8a1, Cas8a2, Cas8b, Cas8c,Cas9 (Csn1 or Csx12), Cas10, Cas10d, CasF, CasG, CasH, Csy1, Csy2, Csy3,Cse1 (CasA), Cse2 (CasB), Cse3 (CasE), Cse4 (CasC), Csc1, Csc2, Csa5,Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csb1,Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx15, Csf1,Csf2, Csf3, Csf4, and Cu1966, and homologs or modified versions thereof.In some embodiments, a Cas system, such as Cas12a, can have multiplegRNAs encoded into a single crRNA. Cas proteins can also be operablylinked to heterologous polypeptides as fusion proteins. For example, aCas protein can be fused to a cleavage domain, an epigeneticmodification domain, a transcriptional activation domain, or atranscriptional repressor domain. Cas proteins can be provided in anyform. For example, a Cas protein can be provided in the form of aprotein, such as a Cas protein complexed with a gRNA. Alternately, a Casprotein can be provided in the form of a nucleic acid molecule encodingthe Cas protein, such as an RNA or DNA.

In some embodiments, targeted genetic modifications of INHBE genomicnucleic acid molecules can be generated by contacting a cell with a Casprotein and one or more gRNAs that hybridize to one or more gRNArecognition sequences within a target genomic locus in the INHBE genomicnucleic acid molecule. For example, a gRNA recognition sequence can belocated within a region of SEQ ID NO:1. The gRNA recognition sequencecan include or be proximate to the start codon of an INHBE genomicnucleic acid molecule or the stop codon of an INHBE genomic nucleic acidmolecule. For example, the gRNA recognition sequence can be located fromabout 10, from about 20, from about 30, from about 40, from about 50,from about 100, from about 200, from about 300, from about 400, fromabout 500, or from about 1,000 nucleotides of the start codon or thestop codon.

The gRNA recognition sequences within a target genomic locus in an INHBEgenomic nucleic acid molecule are located near a Protospacer AdjacentMotif (PAM) sequence, which is a 2-6 base pair DNA sequence immediatelyfollowing the DNA sequence targeted by the Cas9 nuclease. The canonicalPAM is the sequence 5′-NGG-3′ where “N” is any nucleobase followed bytwo guanine (“G”) nucleobases. gRNAs can transport Cas9 to anywhere inthe genome for gene editing, but no editing can occur at any site otherthan one at which Cas9 recognizes PAM. In addition, 5′-NGA-3′ can be ahighly efficient non-canonical PAM for human cells. Generally, the PAMis about 2-6 nucleotides downstream of the DNA sequence targeted by thegRNA. The PAM can flank the gRNA recognition sequence. In someembodiments, the gRNA recognition sequence can be flanked on the 3′ endby the PAM. In some embodiments, the gRNA recognition sequence can beflanked on the 5′ end by the PAM. For example, the cleavage site of Casproteins can be about 1 to about 10, about 2 to about 5 base pairs, orthree base pairs upstream or downstream of the PAM sequence. In someembodiments (such as when Cas9 from S. pyogenes or a closely relatedCas9 is used), the PAM sequence of the non-complementary strand can be5′-NGG-3′, where N is any DNA nucleotide and is immediately 3′ of thegRNA recognition sequence of the non-complementary strand of the targetDNA. As such, the PAM sequence of the complementary strand would be5′-CCN-3′, where N is any DNA nucleotide and is immediately 5′ of thegRNA recognition sequence of the complementary strand of the target DNA.

A gRNA is an RNA molecule that binds to a Cas protein and targets theCas protein to a specific location within an INHBE genomic nucleic acidmolecule. An exemplary gRNA is a gRNA effective to direct a Cas enzymeto bind to or cleave an INHBE genomic nucleic acid molecule, wherein thegRNA comprises a DNA-targeting segment that hybridizes to a gRNArecognition sequence within the INHBE genomic nucleic acid molecule.Exemplary gRNAs comprise a DNA-targeting segment that hybridizes to agRNA recognition sequence present within an INHBE genomic nucleic acidmolecule that includes or is proximate to the start codon or the stopcodon. For example, a gRNA can be selected such that it hybridizes to agRNA recognition sequence that is located from about 5, from about 10,from about 15, from about 20, from about 25, from about 30, from about35, from about 40, from about 45, from about 50, from about 100, fromabout 200, from about 300, from about 400, from about 500, or from about1,000 nucleotides of the start codon or located from about 5, from about10, from about 15, from about 20, from about 25, from about 30, fromabout 35, from about 40, from about 45, from about 50, from about 100,from about 200, from about 300, from about 400, from about 500, or fromabout 1,000 nucleotides of the stop codon. Suitable gRNAs can comprisefrom about 17 to about 25 nucleotides, from about 17 to about 23nucleotides, from about 18 to about 22 nucleotides, or from about 19 toabout 21 nucleotides. In some embodiments, the gRNAs can comprise 20nucleotides.

Examples of suitable gRNA recognition sequences located within the humanINHBE reference gene are set forth in Table 5 as SEQ ID NOs:9-27.

TABLE 5 Guide RNA Recognition Sequences Near INHBE Variation(s) StrandgRNA Recognition Sequence SEQ ID NO: − CGTCTGTTGAGTCTGATTGC 9 +GACGGAGCAACTGCCATCCG 10 − ATCAGGGAGCCGCATGCTCC 11 + CTGAACCAGGGCCATTCACC12 − CCTGGTTCAGGAGCCTCGGA 13 + CATCCGAGGCTCCTGAACCA 14 +CCATCCGAGGCTCCTGAACC 15 − GCCACCTGTCTTCTATTGTC 16 − AGCCGCATGCTCCTGGTGAA17 − GTCTGTTGAGTCTGATTGCT 18 + AAGACAGGTGGCTGTACCCT 19 −CTGATTGCTGGGGGCCAATG 20 − TGATTGCTGGGGGCCAATGA 21 − CCACCTGTCTTCTATTGTCT22 − ATGCTCCTGGTGAATGGCCC 23 − CTGTTGAGTCTGATTGCTGG 24 −CTGGTGAATGGCCCTGGTTC 25 − ACCACTGCCACACCTACCCT 26 − TCTGTTGAGTCTGATTGCTG27

The Cas protein and the gRNA form a complex, and the Cas protein cleavesthe target INHBE genomic nucleic acid molecule. The Cas protein cancleave the nucleic acid molecule at a site within or outside of thenucleic acid sequence present in the target INHBE genomic nucleic acidmolecule to which the DNA-targeting segment of a gRNA will bind. Forexample, formation of a CRISPR complex (comprising a gRNA hybridized toa gRNA recognition sequence and complexed with a Cas protein) can resultin cleavage of one or both strands in or near (such as, for example,within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, or more base pairs from)the nucleic acid sequence present in the INHBE genomic nucleic acidmolecule to which a DNA-targeting segment of a gRNA will bind.

Such methods can result, for example, in an INHBE genomic nucleic acidmolecule in which a region of SEQ ID NO:1 is disrupted, the start codonis disrupted, the stop codon is disrupted, or the coding sequence isdisrupted or deleted. Optionally, the cell can be further contacted withone or more additional gRNAs that hybridize to additional gRNArecognition sequences within the target genomic locus in the INHBEgenomic nucleic acid molecule. By contacting the cell with one or moreadditional gRNAs (such as, for example, a second gRNA that hybridizes toa second gRNA recognition sequence), cleavage by the Cas protein cancreate two or more double-strand breaks or two or more single-strandbreaks.

The methods and compositions disclosed herein can utilize exogenousdonor sequences (e.g., targeting vectors or repair templates) to modifyan INHBE gene, either without cleavage of the INHBE gene or followingcleavage of the INHBE gene with a nuclease agent. An exogenous donorsequence refers to any nucleic acid or vector that includes the elementsthat are required to enable site-specific recombination with a targetsequence. Using exogenous donor sequences in combination with nucleaseagents may result in more precise modifications within the INHBE gene bypromoting homology-directed repair.

In such methods, the nuclease agent cleaves the INHBE gene to create asingle-strand break (nick) or double-strand break, and the exogenousdonor sequence recombines the INHBE gene via non-homologous end joining(NHEJ)-mediated ligation or through a homology-directed repair event.Optionally, repair with the exogenous donor sequence removes or disruptsthe nuclease cleavage site so that alleles that have been targetedcannot be re-targeted by the nuclease agent.

Exogenous donor sequences can comprise deoxyribonucleic acid (DNA) orribonucleic acid (RNA), they can be single-stranded or double-stranded,and they can be in linear or circular form. For example, an exogenousdonor sequence can be a single-stranded oligodeoxynucleotide (ssODN).See, e.g., Yoshimi et al., Nat. Commun., 2016, 7, 10431. An exemplaryexogenous donor sequence is from about 50 nucleotides to about 5 kb inlength, from about 50 nucleotides to about 3 kb in length, or from about50 to about 1,000 nucleotides in length. Other exemplary exogenous donorsequences are from about 40 to about 200 nucleotides in length. Forexample, an exogenous donor sequence can be from about 50 to about 60,from about 60 to about 70, from about 70 to about 80, from about 80 toabout 90, from about 90 to about 100, from about 100 to about 110, fromabout 110 to about 120, from about 120 to about 130, from about 130 toabout 140, from about 140 to about 150, from about 150 to about 160,from about 160 to about 170, from about 170 to about 180, from about 180to about 190, or from about 190 to about 200 nucleotides in length.Alternately, an exogenous donor sequence can be from about 50 to about100, from about 100 to about 200, from about 200 to about 300, fromabout 300 to about 400, from about 400 to about 500, from about 500 toabout 600, from about 600 to about 700, from about 700 to about 800,from about 800 to about 900, or from about 900 to about 1,000nucleotides in length. Alternately, an exogenous donor sequence can befrom about 1 kb to about 1.5 kb, from about 1.5 kb to about 2 kb, fromabout 2 kb to about 2.5 kb, from about 2.5 kb to about 3 kb, from about3 kb to about 3.5 kb, from about 3.5 kb to about 4 kb, from about 4 kbto about 4.5 kb, or from about 4.5 kb to about 5 kb in length.Alternately, an exogenous donor sequence can be, for example, no morethan 5 kb, 4.5 kb, 4 kb, 3.5 kb, 3 kb, 2.5 kb, 2 kb, 1.5 kb, 1 kb, 900nucleotides, 800 nucleotides, 700 nucleotides, 600 nucleotides, 500nucleotides, 400 nucleotides, 300 nucleotides, 200 nucleotides, 100nucleotides, or 50 nucleotides in length.

In some examples, an exogenous donor sequence is an ssODN that is fromabout 80 nucleotides and about 200 nucleotides in length (e.g., about120 nucleotides in length). In another example, an exogenous donorsequences is an ssODN that is from about 80 nucleotides and about 3 kbin length. Such an ssODN can have homology arms, for example, that areeach from about 40 nucleotides and about 60 nucleotides in length. Suchan ssODN can also have homology arms, for example, that are each fromabout 30 nucleotides and 100 nucleotides in length. The homology armscan be symmetrical (e.g., each 40 nucleotides or each 60 nucleotides inlength), or they can be asymmetrical (e.g., one homology arm that is 36nucleotides in length, and one homology arm that is 91 nucleotides inlength).

Exogenous donor sequences can include modifications or sequences thatprovide for additional desirable features (e.g., modified or regulatedstability; tracking or detecting with a fluorescent label; a bindingsite for a protein or protein complex; and so forth). Exogenous donorsequences can comprise one or more fluorescent labels, purificationtags, epitope tags, or a combination thereof. For example, an exogenousdonor sequence can comprise one or more fluorescent labels (e.g.,fluorescent proteins or other fluorophores or dyes), such as at least 1,at least 2, at least 3, at least 4, or at least 5 fluorescent labels.Exemplary fluorescent labels include fluorophores such as fluorescein(e.g., 6-carboxyfluorescein (6-FAM)), Texas Red, HEX, Cy3, Cy5, Cy5.5,Pacific Blue, 5-(and-6)-carboxytetramethylrhodamine (TAMRA), and Cy7. Awide range of fluorescent dyes are available commercially for labelingoligonucleotides (e.g., from Integrated DNA Technologies). Suchfluorescent labels (e.g., internal fluorescent labels) can be used, forexample, to detect an exogenous donor sequence that has been directlyintegrated into a cleaved INHBE gene having protruding ends compatiblewith the ends of the exogenous donor sequence. The label or tag can beat the 5′ end, the 3′ end, or internally within the exogenous donorsequence. For example, an exogenous donor sequence can be conjugated at5′ end with the IR700 fluorophore from Integrated DNA Technologies(5′IRDYE® 700). Exogenous donor sequences can also comprise nucleic acidinserts including segments of DNA to be integrated in the INHBE gene.Integration of a nucleic acid insert in the INHBE gene can result inaddition of a nucleic acid sequence of interest in the INHBE gene,deletion of a nucleic acid sequence of interest in the INHBE gene, orreplacement of a nucleic acid sequence of interest in the INHBE gene(i.e., deletion and insertion). Some exogenous donor sequences aredesigned for insertion of a nucleic acid insert in the INHBE genewithout any corresponding deletion in the INHBE gene. Other exogenousdonor sequences are designed to delete a nucleic acid sequence ofinterest in the INHBE gene without any corresponding insertion of anucleic acid insert. Yet other exogenous donor sequences are designed todelete a nucleic acid sequence of interest in the INHBE gene and replaceit with a nucleic acid insert.

The nucleic acid insert or the corresponding nucleic acid in the INHBEgene being deleted and/or replaced can be various lengths. An exemplarynucleic acid insert or corresponding nucleic acid in the INHBE genebeing deleted and/or replaced is from about 1 nucleotide to about 5 kbin length or is from about 1 nucleotide to about 1,000 nucleotides inlength. For example, a nucleic acid insert or a corresponding nucleicacid in the INHBE gene being deleted and/or replaced can be from about 1to about 10, from about 10 to about 20, from about 20 to about 30, fromabout 30 to about 40, from about 40 to about 50, from about 50 to about60, from about 60 to about 70, from about 70 to about 80, from about 80to about 90, from about 90 to about 100, from about 100 to about 110,from about 110 to about 120, from about 120 to about 130, from about 130to about 140, from about 140 to about 150, from about 150 to about 160,from about 160 to about 170, from about 170 to about 180, from about 180to about 190, or from about 190 to about 200 nucleotides in length.Likewise, a nucleic acid insert or a corresponding nucleic acid in theINHBE gene being deleted and/or replaced can be from about 1 to about100, from about 100 to about 200, from about 200 to about 300, fromabout 300 to about 400, from about 400 to about 500, from about 500 toabout 600, from about 600 to about 700, from about 700 to about 800,from about 800 to about 900, or from about 900 to about 1,000nucleotides in length. Likewise, a nucleic acid insert or acorresponding nucleic acid in the INHBE gene being deleted and/orreplaced can be from about 1 kb to about 1.5 kb, from about 1.5 kb toabout 2 kb, from about 2 kb to about 2.5 kb, from about 2.5 kb to about3 kb, from about 3 kb to about 3.5 kb, from about 3.5 kb to about 4 kb,from about 4 kb to about 4.5 kb, or from about 4.5 kb to about 5 kb inlength.

The nucleic acid insert can comprise genomic DNA or any other type ofDNA. For example, the nucleic acid insert can comprise cDNA.

The nucleic acid insert can comprise a sequence that is homologous toall or part of the INHBE gene (e.g., a portion of the gene encoding aparticular motif or region of an INHBE protein). For example, thenucleic acid insert can comprise a sequence that comprises one or morepoint mutations (e.g., 1, 2, 3, 4, 5, or more) or one or more nucleotideinsertions or deletions compared with a sequence targeted forreplacement in the INHBE gene. The nucleic acid insert or thecorresponding nucleic acid in the INHBE gene being deleted and/orreplaced can be a coding region such as an exon; a non-coding regionsuch as an intron, an untranslated region, or a regulatory region (e.g.,a promoter, an enhancer, or a transcriptional repressor-bindingelement); or any combination thereof.

The nucleic acid insert can also comprise a conditional allele. Theconditional allele can be a multifunctional allele, as described in US2011/0104799. For example, the conditional allele can comprise: a) anactuating sequence in sense orientation with respect to transcription ofa target gene; b) a drug selection cassette (DSC) in sense or antisenseorientation; c) a nucleotide sequence of interest (NSI) in antisenseorientation; and d) a conditional by inversion module (COIN, whichutilizes an exon-splitting intron and an invertible gene-trap-likemodule) in reverse orientation. See, e.g., US 2011/0104799. Theconditional allele can further comprise recombinable units thatrecombine upon exposure to a first recombinase to form a conditionalallele that i) lacks the actuating sequence and the DSC; and ii)contains the NSI in sense orientation and the COIN in antisenseorientation. See, e.g., US 2011/0104799.

Nucleic acid inserts can also comprise a polynucleotide encoding aselection marker. Alternately, the nucleic acid inserts can lack apolynucleotide encoding a selection marker. The selection marker can becontained in a selection cassette. Optionally, the selection cassettecan be a self-deleting cassette. See, e.g., U.S. Pat. No. 8,697,851 andUS 2013/0312129. As an example, the self-deleting cassette can comprisea Cre gene (comprises two exons encoding a Cre recombinase, which areseparated by an intron) operably linked to a mouse Prm1 promoter and aneomycin resistance gene operably linked to a human ubiquitin promoter.Exemplary selection markers include neomycin phosphotransferase(neo^(r)), hygromycin B phosphotransferase (hyg^(r)),puromycin-N-acetyltransferase (puro^(r)), blasticidin S deaminase(bsr^(r)), xanthine/guanine phosphoribosyl transferase (gpt), or herpessimplex virus thymidine kinase (HSV-k), or a combination thereof. Thepolynucleotide encoding the selection marker can be operably linked to apromoter active in a cell being targeted. Examples of promoters aredescribed elsewhere herein.

The nucleic acid insert can also comprise a reporter gene. Exemplaryreporter genes include those encoding luciferase, β-galactosidase, greenfluorescent protein (GFP), enhanced green fluorescent protein (eGFP),cyan fluorescent protein (CFP), yellow fluorescent protein (YFP),enhanced yellow fluorescent protein (eYFP), blue fluorescent protein(BFP), enhanced blue fluorescent protein (eBFP), DsRed, ZsGreen, MmGFP,mPlum, mCherry, tdTomato, mStrawberry, J-Red, mOrange, mKO, mCitrine,Venus, YPet, Emerald, CyPet, Cerulean, T-Sapphire, and alkalinephosphatase. Such reporter genes can be operably linked to a promoteractive in a cell being targeted. Examples of promoters are describedelsewhere herein.

The nucleic acid insert can also comprise one or more expressioncassettes or deletion cassettes. A given cassette can comprise one ormore of a nucleotide sequence of interest, a polynucleotide encoding aselection marker, and a reporter gene, along with various regulatorycomponents that influence expression. Examples of selectable markers andreporter genes that can be included are discussed in detail elsewhereherein. The nucleic acid insert can comprise a nucleic acid flanked withsite-specific recombination target sequences. Alternately, the nucleicacid insert can comprise one or more site-specific recombination targetsequences. Although the entire nucleic acid insert can be flanked bysuch site-specific recombination target sequences, any region orindividual polynucleotide of interest within the nucleic acid insert canalso be flanked by such sites. Site-specific recombination targetsequences, which can flank the nucleic acid insert or any polynucleotideof interest in the nucleic acid insert can include, for example, loxP,lox511, lox2272, lox66, lox71, loxM2, lox5171, FRT, FRT11, FRT71, attp,att, FRT, rox, or a combination thereof. In some examples, thesite-specific recombination sites flank a polynucleotide encoding aselection marker and/or a reporter gene contained within the nucleicacid insert. Following integration of the nucleic acid insert in theINHBE gene, the sequences between the site-specific recombination sitescan be removed. Optionally, two exogenous donor sequences can be used,each with a nucleic acid insert comprising a site-specific recombinationsite. The exogenous donor sequences can be targeted to 5′ and 3′ regionsflanking a nucleic acid of interest. Following integration of the twonucleic acid inserts into the target genomic locus, the nucleic acid ofinterest between the two inserted site-specific recombination sites canbe removed.

Nucleic acid inserts can also comprise one or more restriction sites forrestriction endonucleases (i.e., restriction enzymes), which includeType I, Type II, Type III, and Type IV endonucleases. Type I and TypeIII restriction endonucleases recognize specific recognition sequences,but typically cleave at a variable position from the nuclease bindingsite, which can be hundreds of base pairs away from the cleavage site(recognition sequence). In Type II systems the restriction activity isindependent of any methylase activity, and cleavage typically occurs atspecific sites within or near to the binding site. Most Type II enzymescut palindromic sequences, however Type IIa enzymes recognizenon-palindromic recognition sequences and cleave outside of therecognition sequence, Type IIb enzymes cut sequences twice with bothsites outside of the recognition sequence, and Type IIs enzymesrecognize an asymmetric recognition sequence and cleave on one side andat a defined distance of about 1-20 nucleotides from the recognitionsequence. Type IV restriction enzymes target methylated DNA. Restrictionenzymes are further described and classified, for example in the REBASEdatabase (webpage at rebase.neb.com; Roberts et al., Nucleic Acids Res.,2003, 31, 418-420; Roberts et al., Nucleic Acids Res., 2003, 31,1805-1812; and Belfort et al., in Mobile DNA II, 2002, pp. 761-783, Eds.Craigie et al., (ASM Press, Washington, D.C.)).

Some exogenous donor sequences have short single-stranded regions at the5′ end and/or the 3′ end that are complementary to one or more overhangscreated by nuclease-mediated or Cas-protein-mediated cleavage at thetarget genomic locus (e.g., in the INHBE gene). These overhangs can alsobe referred to as 5′ and 3′ homology arms. For example, some exogenousdonor sequences have short single-stranded regions at the 5′ end and/orthe 3′ end that are complementary to one or more overhangs created byCas-protein-mediated cleavage at 5′ and/or 3′ target sequences at thetarget genomic locus. Some such exogenous donor sequences have acomplementary region only at the 5′ end or only at the 3′ end. Forexample, some such exogenous donor sequences have a complementary regiononly at the 5′ end complementary to an overhang created at a 5′ targetsequence at the target genomic locus or only at the 3′ end complementaryto an overhang created at a 3′ target sequence at the target genomiclocus. Other such exogenous donor sequences have complementary regionsat both the 5′ and 3′ ends. For example, other such exogenous donorsequences have complementary regions at both the 5′ and 3′ ends e.g.,complementary to first and second overhangs, respectively, generated byCas-mediated cleavage at the target genomic locus. For example, if theexogenous donor sequence is double-stranded, the single-strandedcomplementary regions can extend from the 5′ end of the top strand ofthe donor sequence and the 5′ end of the bottom strand of the donorsequence, creating 5′ overhangs on each end. Alternately, thesingle-stranded complementary region can extend from the 3′ end of thetop strand of the donor sequence and from the 3′ end of the bottomstrand of the template, creating 3′ overhangs.

The complementary regions can be of any length sufficient to promoteligation between the exogenous donor sequence and the INHBE gene.Exemplary complementary regions are from about 1 to about 5 nucleotidesin length, from about 1 to about 25 nucleotides in length, or from about5 to about 150 nucleotides in length. For example, a complementaryregion can be at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides in length.Alternately, the complementary region can be from about 5 to about 10,from about 10 to about 20, from about 20 to about 30, from about 30 toabout 40, from about 40 to about 50, from about 50 to about 60, fromabout 60 to about 70, from about 70 to about 80, from about 80 to about90, from about 90 to about 100, from about 100 to about 110, from about110 to about 120, from about 120 to about 130, from about 130 to about140, from about 140 to about 150 nucleotides in length, or longer.

Such complementary regions can be complementary to overhangs created bytwo pairs of nickases. Two double-strand breaks with staggered ends canbe created by using first and second nickases that cleave oppositestrands of DNA to create a first double-strand break, and third andfourth nickases that cleave opposite strands of DNA to create a seconddouble-strand break. For example, a Cas protein can be used to nickfirst, second, third, and fourth guide RNA recognition sequencescorresponding with first, second, third, and fourth guide RNAs. Thefirst and second guide RNA recognition sequences can be positioned tocreate a first cleavage site such that the nicks created by the firstand second nickases on the first and second strands of DNA create adouble-strand break (i.e., the first cleavage site comprises the nickswithin the first and second guide RNA recognition sequences). Likewise,the third and fourth guide RNA recognition sequences can be positionedto create a second cleavage site such that the nicks created by thethird and fourth nickases on the first and second strands of DNA createa double-strand break (i.e., the second cleavage site comprises thenicks within the third and fourth guide RNA recognition sequences).Preferably, the nicks within the first and second guide RNA recognitionsequences and/or the third and fourth guide RNA recognition sequencescan be off-set nicks that create overhangs. The offset window can be,for example, at least about 5 bp, 10 bp, 20 bp, 30 bp, 40 bp, 50 bp, 60bp, 70 bp, 80 bp, 90 bp, 100 bp or more. See, Ran et al., Cell, 2013,154, 1380-1389; Mali et al., Nat. Biotech., 2013, 31, 833-838; and Shenet al., Nat. Methods, 2014, 11, 399-404. In such cases, adouble-stranded exogenous donor sequence can be designed withsingle-stranded complementary regions that are complementary to theoverhangs created by the nicks within the first and second guide RNArecognition sequences and by the nicks within the third and fourth guideRNA recognition sequences. Such an exogenous donor sequence can then beinserted by non-homologous-end-joining-mediated ligation.

Some exogenous donor sequences (i.e., targeting vectors) comprisehomology arms. If the exogenous donor sequence also comprises a nucleicacid insert, the homology arms can flank the nucleic acid insert. Forease of reference, the homology arms are referred to herein as 5′ and 3′(i.e., upstream and downstream) homology arms. This terminology relatesto the relative position of the homology arms to the nucleic acid insertwithin the exogenous donor sequence. The 5′ and 3′ homology armscorrespond to regions within the INHBE gene, which are referred toherein as “5′ target sequence” and “3′ target sequence,” respectively.

A homology arm and a target sequence “correspond” or are “corresponding”to one another when the two regions share a sufficient level of sequenceidentity to one another to act as substrates for a homologousrecombination reaction. The term “homology” includes DNA sequences thatare either identical or share sequence identity to a correspondingsequence. The sequence identity between a given target sequence and thecorresponding homology arm found in the exogenous donor sequence can beany degree of sequence identity that allows for homologous recombinationto occur. For example, the amount of sequence identity shared by thehomology arm of the exogenous donor sequence (or a fragment thereof) andthe target sequence (or a fragment thereof) can be at least 50%, 55%,60%, 65%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequenceidentity, such that the sequences undergo homologous recombination.Moreover, a corresponding region of homology between the homology armand the corresponding target sequence can be of any length that issufficient to promote homologous recombination. Exemplary homology armsare from about 25 nucleotides to about 2.5 kb in length, are from about25 nucleotides to about 1.5 kb in length, or are from about 25 to about500 nucleotides in length. For example, a given homology arm (or each ofthe homology arms) and/or corresponding target sequence can comprisecorresponding regions of homology that are from about 25 to about 30,from about 30 to about 40, from about 40 to about 50, from about 50 toabout 60, from about 60 to about 70, from about 70 to about 80, fromabout 80 to about 90, from about 90 to about 100, from about 100 toabout 150, from about 150 to about 200, from about 200 to about 250,from about 250 to about 300, from about 300 to about 350, from about 350to about 400, from about 400 to about 450, or from about 450 to about500 nucleotides in length, such that the homology arms have sufficienthomology to undergo homologous recombination with the correspondingtarget sequences within the INHBE gene. Alternately, a given homologyarm (or each homology arm) and/or corresponding target sequence cancomprise corresponding regions of homology that are from about 0.5 kb toabout 1 kb, from about 1 kb to about 1.5 kb, from about 1.5 kb to about2 kb, or from about 2 kb to about 2.5 kb in length. For example, thehomology arms can each be about 750 nucleotides in length. The homologyarms can be symmetrical (each about the same size in length), or theycan be asymmetrical (one longer than the other).

The homology arms can correspond to a locus that is native to a cell(e.g., the targeted locus). Alternately, for example, they cancorrespond to a region of a heterologous or exogenous segment of DNAthat was integrated into the genome of the cell, including, for example,transgenes, expression cassettes, or heterologous or exogenous regionsof DNA. Alternately, the homology arms of the targeting vector cancorrespond to a region of a yeast artificial chromosome (YAC), abacterial artificial chromosome (BAC), a human artificial chromosome, orany other engineered region contained in an appropriate host cell. Stillfurther, the homology arms of the targeting vector can correspond to orbe derived from a region of a BAC library, a cosmid library, or a P1phage library, or can be derived from synthetic DNA.

When a nuclease agent is used in combination with an exogenous donorsequence, the 5′ and 3′ target sequences are preferably located insufficient proximity to the nuclease cleavage site so as to promote theoccurrence of a homologous recombination event between the targetsequences and the homology arms upon a single-strand break (nick) ordouble-strand break at the nuclease cleavage site. The term “nucleasecleavage site” includes a DNA sequence at which a nick or double-strandbreak is created by a nuclease agent (e.g., a Cas9 protein complexedwith a guide RNA). The target sequences within the INHBE gene thatcorrespond to the 5′ and 3′ homology arms of the exogenous donorsequence are “located in sufficient proximity” to a nuclease cleavagesite if the distance is such as to promote the occurrence of ahomologous recombination event between the 5′ and 3′ target sequencesand the homology arms upon a single-strand break or double-strand breakat the nuclease cleavage site. Thus, the target sequences correspondingto the 5′ and/or 3′ homology arms of the exogenous donor sequence canbe, for example, within at least 1 nucleotide of a given nucleasecleavage site or within at least 10 nucleotides to about 1,000nucleotides of a given nuclease cleavage site. As an example, thenuclease cleavage site can be immediately adjacent to at least one orboth of the target sequences.

The spatial relationship of the target sequences that correspond to thehomology arms of the exogenous donor sequence and the nuclease cleavagesite can vary. For example, target sequences can be located 5′ to thenuclease cleavage site, target sequences can be located 3′ to thenuclease cleavage site, or the target sequences can flank the nucleasecleavage site.

Also provided are therapeutic methods and methods of treatment orprophylaxis of a metabolic disorder in a subject having or at risk forthe disease using the methods disclosed herein for modifying or alteringexpression of an endogenous INHBE gene. Also provided are therapeuticmethods and methods of treatment or prophylaxis of a metabolic disorderin a subject having or at risk for the disease using methods fordecreasing expression of INHBE mRNA transcripts or using methods forproviding recombinant nucleic acids encoding INHBE proteins, providingmRNAs encoding INHBE proteins, or providing INHBE proteins to thesubject. The methods can comprise introducing one or more nucleic acidsor proteins into the subject, into the liver of the subject, or into acell (e.g., liver cell) of the subject (e.g., in vivo or ex vivo).

Also provided are therapeutic methods and methods of treatment orprophylaxis of a cardiovascular disease in a subject having or at riskfor cardiovascular disease using the methods disclosed herein formodifying or altering expression of an endogenous INHBE gene. Alsoprovided are therapeutic methods and methods of treatment or prophylaxisof a cardiovascular disease in a subject having or at risk forcardiovascular disease using methods for decreasing expression of INHBEmRNA transcripts or using methods for providing recombinant nucleicacids encoding INHBE proteins, providing mRNAs encoding INHBE proteins,or providing INHBE proteins to the subject. The methods can compriseintroducing one or more nucleic acids or proteins into the subject, intothe liver of the subject, or into a cell (e.g., liver cell) of thesubject (e.g., in vivo or ex vivo).

Such methods can comprise genome editing or gene therapy. For example,an endogenous INHBE gene that does not encode a loss-of-function variantcan be modified to comprise any of the loss-of-function variantsdescribed herein. As another example, an endogenous INHBE gene that doesnot encode a loss-of-function variant can be knocked out or inactivated.Likewise, an endogenous INHBE gene that does not encode aloss-of-function variant can be knocked out or inactivated, and an INHBEgene comprising any one of or any combination of the INHBEloss-of-function variants described herein can be introduced andexpressed. Similarly, an endogenous INHBE gene that does not encode aloss-of-function variant can be knocked out or inactivated, and arecombinant DNA encoding any one of or any combination of the INHBEloss-of-function variants described herein can be introduced andexpressed, an mRNA encoding any one of or any combination of INHBEloss-of-function variants described herein (or fragments thereof) can beintroduced and expressed (e.g., intracellular protein replacementtherapy), or a cDNA encoding any one of or any combination of INHBEloss-of-function variants described herein (or fragments thereof) can beintroduced (e.g., protein replacement therapy).

Other such methods can comprise introducing and expressing a recombinantINHBE gene comprising any one of or any combination of INHBEloss-of-function variants described herein (e.g., the full INHBE variantor a minigene comprising the modification), introducing and expressingrecombinant nucleic acids (e.g., DNA) encoding any one of or anycombination of INHBE loss-of-function variants described herein orfragments thereof, introducing and expressing one or more mRNAs encodingany one of or any combination of INHBE loss-of-function variantsdescribed herein fragments thereof (e.g., intracellular proteinreplacement therapy), or introducing any one of or any combination ofINHBE loss-of-function variants described herein (e.g., proteinreplacement therapy) without knocking out or inactivating an endogenousINHBE gene that does not encode a loss-of-function variant.

An INHBE gene or minigene or a DNA encoding any one of or anycombination of INHBE loss-of-function variants described herein orfragments thereof can be introduced and expressed in the form of anexpression vector that does not modify the genome, it can be introducedin the form of a targeting vector such that it genomically integratesinto an INHBE locus, or it can be introduced such that it genomicallyintegrates into a locus other than the INHBE locus, such as a safeharbor locus. The genomically integrated INHBE gene can be operablylinked to an INHBE promoter or to another promoter, such as anendogenous promoter at the site of integration. Safe harbor loci arechromosomal sites where transgenes can be stably and reliably expressedin all tissues of interest without adversely affecting gene structure orexpression. Safe harbor loci can have, for example, one or more or allof the following characteristics: distance of greater than 50 kb fromthe 5′ end of any gene; distance of greater than 300 kb from anycancer-related gene; distance of greater than 300 kb from any microRNA;outside a gene transcription unit, and outside of ultra-conservedregions. Examples of suitable safe harbor loci include adeno-associatedvirus site 1 (AAVS1), the chemokine (CC motif) receptor 5 (CCR5) genelocus, and the human orthologue of mouse ROSA26 locus.

Combinations of INHBE protein isoforms or nucleic acids encoding INHBEprotein isoforms that can be introduced and expressed include, any oneor any combination of protein or mRNA isoforms described herein. Forexample, INHBE a nucleic acid encoding Isoform 1 (SEQ ID NO:2) encodingany one or any combination of loss-of-function variants described herein(alone or in combination with other isoforms) is introduced orexpressed. Exemplary sequences for each of these isoforms andtranscripts are provided elsewhere herein. It is understood, however,that gene sequences and within a population, mRNA sequences transcribedfrom such genes, and proteins translated from such mRNAs can vary due topolymorphisms such as single-nucleotide polymorphisms. The sequencesprovided herein for each transcript and isoform are only exemplarysequences. Other sequences are also possible.

In some embodiments, the methods comprise treating a subject who is nota carrier of any of the INHBE variant nucleic acid molecules describedherein (or is only a heterozygous carrier of any one or any combinationof the variant nucleic acid molecules described herein) and has or issusceptible to developing a metabolic disorder and/or a cardiovasculardisease, comprising introducing into the subject or introducing into aliver cell in the subject: a) a nuclease agent (or nucleic acidencoding) that binds to a nuclease recognition sequence within an INHBEgene, wherein the nuclease recognition sequence includes or is proximateto a position of one of the INHBE variant nucleic acid moleculesdescribed herein; and b) an exogenous donor sequence comprising a 5′homology arm that hybridizes to a target sequence 5′ of the position ofone of the INHBE variant nucleic acid molecules described herein, a 3′homology arm that hybridizes to a target sequence 3′ of the same INHBEvariant nucleic acid molecule, and a nucleic acid insert comprising oneor more of the variant nucleotides flanked by the 5′ homology arm andthe 3′ homology arm. The nuclease agent can cleave the INHBE gene in aliver cell in the subject, and the exogenous donor sequence canrecombine with the INHBE gene in the liver cell, wherein uponrecombination of the exogenous donor sequence with the INHBE gene thenucleic acid insert encoding the loss-of-function variant is introduced,substituting the wild type nucleotide. Examples of nuclease agents(e.g., a Cas9 protein and a guide RNA) that can be used in such methodsare disclosed elsewhere herein. Examples of suitable guide RNAs andguide RNA recognition sequences are disclosed elsewhere herein. Examplesof exogenous donor sequences that can be used in such methods aredisclosed elsewhere herein.

As another example, the methods can comprise treating a subject who isnot a carrier of any of the INHBE variant nucleic acid moleculesdescribed herein (or is only a heterozygous carrier of any one or anycombination of the variant nucleic acid molecules described herein) andhas or is susceptible to developing a metabolic disorder and/or acardiovascular disease, comprising introducing into the subject orintroducing into a liver cell in the subject an exogenous donor sequencecomprising a 5′ homology arm that hybridizes to a target sequence 5′ ofthe position of one of the INHBE variant nucleic acid moleculesdescribed herein, a 3′ homology arm that hybridizes to a target sequence3′ of the same INHBE variant nucleic acid molecule, and a nucleic acidinsert comprising one or more of the variant nucleotides flanked by the5′ homology arm and the 3′ homology arm. The exogenous donor sequencecan recombine with the INHBE gene in the liver cell, wherein uponrecombination of the exogenous donor sequence with the INHBE gene thenucleic acid insert encoding the loss-of-function variant is introduced,substituting the wild type nucleotide. Examples of exogenous donorsequences that can be used in such methods are disclosed elsewhereherein.

In some embodiments, the methods comprise treating a subject who is nota carrier of any of the INHBE variant nucleic acid molecules describedherein (or is only a heterozygous carrier of any one or any combinationof the variant nucleic acid molecules described herein) and has or issusceptible to developing a metabolic disorder and/or a cardiovasculardisease, comprising introducing into the subject or introducing into aliver cell in the subject: a) a nuclease agent (or nucleic acidencoding) that binds to a nuclease recognition sequence within an INHBEgene, wherein the nuclease recognition sequence comprises the startcodon for the INHBE gene or is within about 10, 20, 30, 40, 50, 100,200, 300, 400, 500, or 1,000 nucleotides of the start codon. Thenuclease agent can cleave and disrupt expression of the INHBE gene in aliver cell in the subject. In some embodiments, the methods comprisetreating a subject who is not a carrier of any of the INHBE variantnucleic acid molecules described herein (or is only a heterozygouscarrier of any one or any combination of the INHBE variant nucleic acidmolecules described herein) and has or is susceptible to developing ametabolic disorder and/or a cardiovascular disease, comprisingintroducing into the subject or introducing into a liver cell in thesubject: a) a nuclease agent (or nucleic acid encoding) that binds to anuclease recognition sequence within an INHBE gene, wherein the nucleaserecognition sequence comprises the start codon for the INHBE gene or iswithin about 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, or 1,000nucleotides of the start codon or is selected from SEQ ID NOs: 1-7; andb) an expression vector comprising a recombinant INHBE gene comprisingany one or any combination of loss-of-function variants describedherein. The expression vector can be one that does not genomicallyintegrate. Alternately, a targeting vector (i.e., exogenous donorsequence) can be introduced comprising a recombinant INHBE genecomprising any one or any combination of loss-of-function variantsdescribed herein. The nuclease agent can cleave and disrupt expressionof the INHBE gene in a liver cell in the subject, and the expressionvector can express the recombinant INHBE gene in the liver cell in thesubject. Alternately, the genomically integrated, recombinant INHBE genecan express in the liver cell in the subject. Examples of nucleaseagents (e.g., a nuclease-active Cas9 protein and guide RNA) that can beused in such methods are disclosed elsewhere herein. Examples ofsuitable guide RNAs and guide RNA recognition sequences are disclosedelsewhere herein. Step b) can Alternately comprise introducing anexpression vector or targeting vector comprising a nucleic acid (e.g.,DNA) encoding an INHBE protein that is at least 90%, at least 95%, atleast 96%, at least 97%, at least 98%, at least 99%, or 100% identicalto any INHBE isoform described herein or a fragment thereof andcomprising any one or any combination of the INHBE variant nucleic acidmolecules described herein. Likewise, step b) can alternately compriseintroducing an mRNA encoding an INHBE protein that is at least 90%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identical to any INHBE mRNA isoform described herein or a fragmentthereof and comprising any one or any combination of the INHBE variantnucleic acid molecules described herein. Likewise, step b) canalternately comprise introducing a protein comprising a sequence that isat least 90%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identical to any INHBE protein isoform describedherein or a fragment thereof and comprising any one or any combinationof loss-of-function variant polypeptides described herein.

In some embodiments, a second nuclease agent is also introduced into thesubject or into the liver cell in the subject, wherein the secondnuclease agent binds to a second nuclease recognition sequence withinthe INHBE gene, wherein the second nuclease recognition sequencecomprises the stop codon for the INHBE gene or is within about 10, 20,30, 40, 50, 100, 200, 300, 400, 500, or 1,000 nucleotides of the stopcodon, wherein the nuclease agent cleaves the INHBE gene in the livercell within both the first nuclease recognition sequence and the secondnuclease recognition sequence, wherein the liver cell is modified tocomprise a deletion between the first nuclease recognition sequence andthe second nuclease recognition sequence. For example, the secondnuclease agent can be a Cas9 protein and a guide RNA. Suitable guideRNAs and guide RNA recognition sequences in proximity to the stop codonare disclosed elsewhere herein.

Such methods can also comprise a method of treating a subject who is nota carrier of any of the INHBE variant nucleic acid molecules describedherein (or is only a heterozygous carrier of any one or any combinationof the INHBE variant nucleic acid molecules described herein) and has oris susceptible to developing a metabolic disorder and/or acardiovascular disease, comprising introducing into the subject orintroducing into a liver cell in the subject: a) a DNA-binding protein(or nucleic acid encoding) that binds to a DNA-binding proteinrecognition sequence within an INHBE gene, wherein the DNA-bindingprotein recognition sequence comprises the start codon for the INHBEgene or is within about 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, or1,000 nucleotides of the start codon. The DNA-binding protein can alter(e.g., reduce) expression of the INHBE gene in a liver cell in thesubject. Such methods can also comprise a method of treating a subjectwho is not a carrier of any of the INHBE variant nucleic acid moleculesdescribed herein (or is only a heterozygous carrier of any one or anycombination of the INHBE variant nucleic acid molecules describedherein) and has or is susceptible to developing a metabolic disorderand/or a cardiovascular disease, comprising introducing into the subjector introducing into a liver cell in the subject: a) a DNA-bindingprotein (or nucleic acid encoding) that binds to a DNA-binding proteinrecognition sequence within an INHBE gene, wherein the DNA-bindingprotein recognition sequence comprises the start codon for the INHBEgene or is within about 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, or1,000 nucleotides of the start codon; and b) an expression vectorcomprising a recombinant INHBE gene comprising any one or anycombination of loss-of-function variants described herein. Theexpression vector can be one that does not genomically integrate.Alternately, a targeting vector (i.e., exogenous donor sequence) can beintroduced comprising a recombinant INHBE gene comprising any one or anycombination of the INHBE variant nucleic acid molecules describedherein. The DNA-binding protein can alter (e.g., reduce) expression ofthe INHBE gene in a liver cell in the subject, and the expression vectorcan express the recombinant INHBE gene in the liver cell in the subject.Alternately, the genomically integrated, recombinant INHBE gene canexpress in the liver cell in the subject. Examples of DNA-bindingproteins suitable for use in such methods are disclosed elsewhereherein. Such DNA-binding proteins (e.g., Cas9 protein and guide RNA) canbe fused or operably linked to a transcriptional repressor domain. Forexample, the DNA-binding protein can be a catalytically inactive Cas9protein fused to a transcriptional repressor domain. Examples ofsuitable guide RNAs and guide RNA recognition sequences are disclosedelsewhere herein. Step b) can alternately comprise introducing anexpression vector or targeting vector comprising a nucleic acid (e.g.,DNA) encoding an INHBE protein that is at least 90%, at least 95%, atleast 96%, at least 97%, at least 98%, at least 99%, or 100% identicalto any INHBE isoform described herein or a fragment thereof andcomprising any one or any combination of the INHBE variant nucleic acidmolecules described herein. Likewise, step b) can alternately compriseintroducing an mRNA encoding an INHBE protein that is at least 90%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identical any INHBE mRNA isoform described herein or a fragmentthereof and comprising any one or any combination of the INHBE variantnucleic acid molecules described herein. Likewise, step b) canalternately comprise introducing a protein comprising a sequence that isat least 90%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identical to any INHBE protein isoform describedherein or a fragment thereof and comprising any one or any combinationof loss-of-function variant polypeptides described herein.

Other such methods can comprise method of treating a subject who is nota carrier of any of the INHBE variant nucleic acid molecules describedherein (or is only a heterozygous carrier of any one or any combinationof the INHBE variant nucleic acid molecules described herein) and has oris susceptible to developing a metabolic disorder and/or acardiovascular disease, comprising introducing into the subject orintroducing into a liver cell in the subject an expression vector,wherein the expression vector comprises a recombinant INHBE genecomprising any one or any combination of loss-of-function variantsdescribed herein, wherein the expression vector expresses therecombinant INHBE gene in a liver cell in the subject. The expressionvector can be one that does not genomically integrate. Alternately, atargeting vector (i.e., exogenous donor sequence) can be introducedcomprising a recombinant INHBE gene comprising any one or anycombination of the INHBE variant nucleic acid molecules describedherein. In methods in which an expression vector is used, the expressionvector can express the recombinant INHBE gene in the liver cell in thesubject. Alternately, in methods in which a recombinant INHBE gene isgenomically integrated, the recombinant INHBE gene can express in theliver cell in the subject. Such methods can alternately compriseintroducing an expression vector or targeting vector comprising anucleic acid (e.g., DNA) encoding an INHBE protein that is at least 90%,at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identical to any INHBE isoform described herein or a fragmentthereof and comprising any one or any combination of loss-of-functionvariants described herein. Likewise, such methods can alternatelycomprise introducing an mRNA encoding an INHBE protein that is at least90%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identical to any INHBE mRNA isoform described herein or afragment thereof and comprising any one or any combination of the INHBEvariant nucleic acid molecules described herein. Likewise, such methodscan alternately comprise introducing a protein comprising a sequencethat is at least 90%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identical to any INHBE protein isoformdescribed herein or a fragment thereof and comprising any one or anycombination of loss-of-function variant polypeptides described herein.

Suitable expression vectors and recombinant INHBE genes for use in anyof the above methods are disclosed elsewhere herein. For example, therecombinant INHBE gene can be the full length variant gene or can be anINHBE minigene in which one or more nonessential segments of the genehave been deleted with respect to a corresponding wild type INHBE gene.As an example, the deleted segments can comprise one or more intronicsequences. An example of a full INHBE gene is one that is at least 90%,at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%identical to SEQ ID NO:1 when optimally aligned with SEQ ID NO:1.

In some embodiments, the methods comprise modifying a cell (e.g., aliver cell) in a subject having or susceptible to developing a chronicliver disease. In some embodiments, the methods comprise modifying acell (e.g., a cardiac cell) in a subject having or susceptible todeveloping a cardiovascular disease. In such methods, the nucleaseagents and/or exogenous donor sequences and/or recombinant expressionvectors can be introduced into the cell via administration in aneffective regime meaning a dosage, route of administration and frequencyof administration that delays the onset, reduces the severity, inhibitsfurther deterioration, and/or ameliorates at least one sign or symptomof the disease being treated. The term “symptom” refers to a subjectiveevidence of a disease as perceived by the subject, and a “sign” refersto objective evidence of a disease as observed by a physician. If asubject is already suffering from a disease, the regime can be referredto as a therapeutically effective regime. If the subject is at elevatedrisk of the disease relative to the general population but is not yetexperiencing symptoms, the regime can be referred to as aprophylactically effective regime. In some instances, therapeutic orprophylactic efficacy can be observed in an individual patient relativeto historical controls or past experience in the same subject. In otherinstances, therapeutic or prophylactic efficacy can be demonstrated in apreclinical or clinical trial in a population of treated subjectsrelative to a control population of untreated subjects.

Delivery can be any suitable method, as disclosed elsewhere herein. Forexample, the nuclease agents or exogenous donor sequences or recombinantexpression vectors can be delivered by vector delivery, viral delivery,particle-mediated delivery, nanoparticle-mediated delivery,liposome-mediated delivery, exosome-mediated delivery, lipid-mediateddelivery, lipid-nanoparticle-mediated delivery,cell-penetrating-peptide-mediated delivery, orimplantable-device-mediated delivery. Some specific examples includehydrodynamic delivery, virus-mediated delivery, andlipid-nanoparticle-mediated delivery. Administration can be by anysuitable route including, for example, parenteral, intravenous, oral,subcutaneous, intra-arterial, intracranial, intrathecal,intraperitoneal, topical, intranasal, or intramuscular. A specificexample which is often used, for example, for protein replacementtherapies is intravenous infusion. The frequency of administration andthe number of dosages can depend on the half-life of the nuclease agentsor exogenous donor sequences or recombinant expression vectors, thecondition of the subject, and the route of administration among otherfactors. Pharmaceutical compositions for administration are preferablysterile and substantially isotonic and manufactured under GMPconditions. Pharmaceutical compositions can be provided in unit dosageform (i.e., the dosage for a single administration). Pharmaceuticalcompositions can be formulated using one or more physiologically andpharmaceutically acceptable carriers, diluents, excipients orauxiliaries. The formulation depends on the route of administrationchosen. The term “pharmaceutically acceptable” means that the carrier,diluent, excipient, or auxiliary is compatible with the otheringredients of the formulation and not substantially deleterious to therecipient thereof.

Other such methods comprise an ex vivo method in a cell from a subjecthaving or susceptible to developing a chronic liver disease and/or acardiovascular disease. The cell with the targeted genetic modificationcan then be transplanted back into the subject.

In some embodiments, the INHBE inhibitor comprises a small molecule. Insome embodiments, the INHBE inhibitor is any of the inhibitory nucleicacid molecules described herein. In some embodiments, the INHBEinhibitor comprises an antibody.

In some embodiments, the methods of treatment further comprise detectingthe presence or absence of an INHBE variant nucleic acid moleculeencoding an INHBE predicted loss-of-function polypeptide, or thepresence of the corresponding INHBE polypeptide, or the quantificationof the INHBE polypeptide or nucleic acid (such as RNA) in a biologicalsample from the subject. As used throughout the present disclosure, an“an INHBE variant nucleic acid molecule” is any INHBE nucleic acidmolecule (such as, for example, genomic nucleic acid molecule, mRNAmolecule, or cDNA molecule) encoding an INHBE polypeptide having apartial loss-of-function, a complete loss-of-function, a predictedpartial loss-of-function, or a predicted complete loss-of-function.

The present disclosure also provides methods of treating a subject witha therapeutic agent that treats or inhibits a metabolic disorder,wherein the subject is suffering from the metabolic disorder. In someembodiments, the methods comprise determining whether the subject has anINHBE variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide by obtaining or having obtained abiological sample from the subject, and performing or having performed agenotyping assay on the biological sample to determine if the subjecthas a genotype comprising the INHBE variant nucleic acid molecule. Whenthe subject is INHBE reference, the therapeutic agent that treats orinhibits the metabolic disorder is administered or continued to beadministered to the subject in a standard dosage amount, and an INHBEinhibitor is administered to the subject. When the subject isheterozygous for an INHBE variant nucleic acid molecule, the therapeuticagent that treats or inhibits the metabolic disorder is administered orcontinued to be administered to the subject in an amount that is thesame as or lower than a standard dosage amount, and an INHBE inhibitoris administered to the subject. When the subject is homozygous for anINHBE variant nucleic acid molecule, the therapeutic agent that treatsor inhibits the metabolic disorder is administered or continued to beadministered to the subject in an amount that is the same as or lowerthan a standard dosage amount. The presence of a genotype having anINHBE variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide indicates the subject has a decreased riskof developing a metabolic disorder. In some embodiments, the subject isINHBE reference. In some embodiments, the subject is heterozygous for anINHBE variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide.

For subjects that are genotyped or determined to be either INHBEreference or heterozygous for an INHBE variant nucleic acid moleculeencoding an INHBE predicted loss-of-function polypeptide, such subjectscan be treated with an INHBE inhibitor, as described herein.

The present disclosure also provides methods of treating a subject witha therapeutic agent that treats or inhibits a cardiovascular disease,wherein the subject is suffering from the cardiovascular disease. Insome embodiments, the methods comprise determining whether the subjecthas an INHBE variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide by obtaining or having obtained abiological sample from the subject, and performing or having performed agenotyping assay on the biological sample to determine if the subjecthas a genotype comprising the INHBE variant nucleic acid molecule. Whenthe subject is INHBE reference, the therapeutic agent that treats orinhibits the cardiovascular disease is administered or continued to beadministered to the subject in a standard dosage amount, and an INHBEinhibitor is administered to the subject. When the subject isheterozygous for an INHBE variant nucleic acid molecule, the therapeuticagent that treats or inhibits the cardiovascular disease is administeredor continued to be administered to the subject in an amount that is thesame as or lower than a standard dosage amount, and an INHBE inhibitoris administered to the subject. When the subject is homozygous for anINHBE variant nucleic acid molecule, the therapeutic agent that treatsor inhibits the cardiovascular disease is administered or continued tobe administered to the subject in an amount that is the same as or lowerthan a standard dosage amount. The presence of a genotype having anINHBE variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide indicates the subject has a decreased riskof developing a cardiovascular disease. In some embodiments, the subjectis INHBE reference. In some embodiments, the subject is heterozygous foran INHBE variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide.

For subjects that are genotyped or determined to be either INHBEreference or heterozygous for an INHBE variant nucleic acid moleculeencoding an INHBE predicted loss-of-function polypeptide, such subjectscan be treated with an INHBE inhibitor, as described herein.

Detecting the presence or absence of an INHBE variant nucleic acidmolecule encoding an INHBE predicted loss-of-function polypeptide in abiological sample from a subject and/or determining whether a subjecthas an INHBE variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide can be carried out by any of the methodsdescribed herein. In some embodiments, these methods can be carried outin vitro. In some embodiments, these methods can be carried out in situ.In some embodiments, these methods can be carried out in vivo. In any ofthese embodiments, the nucleic acid molecule can be present within acell obtained from the subject.

In some embodiments, when the subject is INHBE reference, the subject isalso administered a therapeutic agent that treats or inhibits ametabolic disorder in a standard dosage amount. In some embodiments,when the subject is heterozygous or homozygous for an INHBE variantnucleic acid molecule encoding an INHBE predicted loss-of-functionpolypeptide, the subject is also administered a therapeutic agent thattreats or inhibits the metabolic disorder in a dosage amount that is thesame as or lower than a standard dosage amount.

In some embodiments, when the subject is INHBE reference, the subject isalso administered a therapeutic agent that treats or inhibits acardiovascular disease in a standard dosage amount. In some embodiments,when the subject is heterozygous or homozygous for an INHBE variantnucleic acid molecule encoding an INHBE predicted loss-of-functionpolypeptide, the subject is also administered a therapeutic agent thattreats or inhibits the cardiovascular disease in a dosage amount that isthe same as or lower than a standard dosage amount.

In some embodiments, the treatment methods further comprise detectingthe presence or absence of an INHBE predicted loss-of-functionpolypeptide in a biological sample from the subject. In someembodiments, when the subject does not have an INHBE predictedloss-of-function polypeptide, the subject is also administered atherapeutic agent that treats or inhibits a metabolic disorder in astandard dosage amount. In some embodiments, when the subject has anINHBE predicted loss-of-function polypeptide, the subject is alsoadministered a therapeutic agent that treats or inhibits the metabolicdisorder in a dosage amount that is the same as or lower than a standarddosage amount.

In some embodiments, the treatment methods further comprise detectingthe presence or absence of an INHBE predicted loss-of-functionpolypeptide in a biological sample from the subject. In someembodiments, when the subject does not have an INHBE predictedloss-of-function polypeptide, the subject is also administered atherapeutic agent that treats or inhibits a cardiovascular disease in astandard dosage amount. In some embodiments, when the subject has anINHBE predicted loss-of-function polypeptide, the subject is alsoadministered a therapeutic agent that treats or inhibits thecardiovascular disease in a dosage amount that is the same as or lowerthan a standard dosage amount.

The present disclosure also provides methods of treating a subject witha therapeutic agent that treats or inhibits a metabolic disorder,wherein the subject is suffering from the metabolic disorder. In someembodiments, the method comprises determining whether the subject has anINHBE predicted loss-of-function polypeptide by obtaining or havingobtained a biological sample from the subject, and performing or havingperformed an assay on the biological sample to determine if the subjecthas an INHBE predicted loss-of-function polypeptide. When the subjectdoes not have an INHBE predicted loss-of-function polypeptide, thetherapeutic agent that treats or inhibits the metabolic disorder isadministered or continued to be administered to the subject in astandard dosage amount, and an INHBE inhibitor is administered to thesubject. When the subject has an INHBE predicted loss-of-functionpolypeptide, the therapeutic agent that treats or inhibits the metabolicdisorder is administered or continued to be administered to the subjectin an amount that is the same as or lower than a standard dosage amount,and an INHBE inhibitor is administered to the subject. The presence ofan INHBE predicted loss-of-function polypeptide indicates the subjecthas a decreased risk of developing a metabolic disorder. In someembodiments, the subject has an INHBE predicted loss-of-functionpolypeptide. In some embodiments, the subject does not have an INHBEpredicted loss-of-function polypeptide.

The present disclosure also provides methods of treating a subject witha therapeutic agent that treats or inhibits a cardiovascular disease,wherein the subject is suffering from the cardiovascular disease. Insome embodiments, the method comprises determining whether the subjecthas an INHBE predicted loss-of-function polypeptide by obtaining orhaving obtained a biological sample from the subject, and performing orhaving performed an assay on the biological sample to determine if thesubject has an INHBE predicted loss-of-function polypeptide. When thesubject does not have an INHBE predicted loss-of-function polypeptide,the therapeutic agent that treats or inhibits the cardiovascular diseaseis administered or continued to be administered to the subject in astandard dosage amount, and an INHBE inhibitor is administered to thesubject. When the subject has an INHBE predicted loss-of-functionpolypeptide, the therapeutic agent that treats or inhibits thecardiovascular disease is administered or continued to be administeredto the subject in an amount that is the same as or lower than a standarddosage amount, and an INHBE inhibitor is administered to the subject.The presence of an INHBE predicted loss-of-function polypeptideindicates the subject has a decreased risk of developing acardiovascular disease. In some embodiments, the subject has an INHBEpredicted loss-of-function polypeptide. In some embodiments, the subjectdoes not have an INHBE predicted loss-of-function polypeptide.

Detecting the presence or absence of an INHBE predicted loss-of-functionpolypeptide in a biological sample from a subject and/or determiningwhether a subject has an INHBE predicted loss-of-function polypeptidecan be carried out by any of the methods described herein. In someembodiments, these methods can be carried out in vitro. In someembodiments, these methods can be carried out in situ. In someembodiments, these methods can be carried out in vivo. In any of theseembodiments, the polypeptide can be present within a cell or bloodsample obtained from the subject, or maybe imputed from otherinformation about the subject that has previously been generated fromcollection of a cell or blood sample from the subject or biologicalrelatives of the subject. In any of these embodiments, determination byquantification of the amount of INHBE polypeptide can be included as adetermination of loss of function due to the effective absence orreduction in the amount of the INHBE polypeptide. In any of theseembodiments, detection, sequencing, and/or quantification of INHBE DNAand RNA can serve as methods for determining INHBE loss of function orabsence of INHBE entirely.

Examples of therapeutic agents that treat or inhibit type 2 diabetesinclude, but are not limited to: metformin, insulin, sulfonylureas (suchas glyburide, glipizide, and glimepiride), meglitinides (such asrepaglinide and nateglinide), thiazolidinediones (such as rosiglitazoneand pioglitazone), DPP-4 inhibitors (such as sitagliptin, saxagliptin,and linagliptin), GLP-1 receptor agonists (such as exenatide,liraglutide, and semaglutide), and SGLT2 inhibitors (such ascanagliflozin, dapagliflozin, and empagliflozin). In some embodiments,the therapeutic agent is metformin, insulin, glyburide, glipizide,glimepiride, repaglinide, nateglinide, rosiglitazone, pioglitazone,sitagliptin, saxagliptin, linagliptin, exenatide, liraglutide,semaglutide, canagliflozin, dapagliflozin, or empagliflozin. In someembodiments, the therapeutic agent is metformin. In some embodiments,the therapeutic agent is insulin. In some embodiments, the therapeuticagent is glyburide. In some embodiments, the therapeutic agent isglipizide. In some embodiments, the therapeutic agent is glimepiride. Insome embodiments, the therapeutic agent is repaglinide. In someembodiments, the therapeutic agent is nateglinide. In some embodiments,the therapeutic agent is rosiglitazone. In some embodiments, thetherapeutic agent is pioglitazone. In some embodiments, the therapeuticagent is sitagliptin. In some embodiments, the therapeutic agent issaxagliptin. In some embodiments, the therapeutic agent is linagliptin.In some embodiments, the therapeutic agent is exenatide. In someembodiments, the therapeutic agent is liraglutide. In some embodiments,the therapeutic agent is semaglutide. In some embodiments, thetherapeutic agent is canagliflozin. In some embodiments, the therapeuticagent is dapagliflozin. In some embodiments, the therapeutic agent isempagliflozin.

Examples of therapeutic agents that treat or inhibit obesity include,but are not limited to: orlistat, phentermine, topiramate, bupropion,naltrexone, and liraglutide. In some embodiments, the therapeutic agentis orlistat. In some embodiments, the therapeutic agent is phentermine.In some embodiments, the therapeutic agent is topiramate. In someembodiments, the therapeutic agent is bupropion. In some embodiments,the therapeutic agent is naltrexone. In some embodiments, thetherapeutic agent is liraglutide.

Examples of therapeutic agents that treat or inhibit elevatedtriglyceride include, but are not limited to: statins (such asrosuvastatin, simvastatin, and atorvastatin), fibrates (such asfenofibrate, gemfibrozil, and fenofibric acid), nicotinic acid (such asniacin), and fatty acids (such as omega-3 fatty acids). In someembodiments, the therapeutic agent is a statin.

Examples of therapeutic agents that treat or inhibit lipodystrophyinclude, but are not limited to: EGRIFTA® (tesamorelin), GLUCOPHAGE®(metformin), SCULPTRA® (poly-L-lactic acid), RADIESSE® (calciumhydroxyapatite), polymethylmethacrylate (e.g., PMMA), ZYDERM® (bovinecollagen), COSMODERM® (human collagen), silicone, glitazones, andhyaluronic acid. In some embodiments, the therapeutic agent that treatsor inhibits lipodystrophy include, but are not limited to: tesamorelin,metformin, poly-L-lactic acid, a calcium hydroxyapatite,polymethylmethacrylate, a bovine collagen, a human collagen, silicone,and hyaluronic acid.

Examples of therapeutic agents that treat or inhibit liver inflammationinclude, but are not limited to hepatitis therapeutics and hepatitisvaccines.

Examples of therapeutic agents or procedures that treat or inhibit fattyliver disease include, but are not limited to, bariatric surgery and/ordietary intervention.

Examples of therapeutic agents that treat or inhibithypercholesterolemia include, but are not limited to: statins (e.g.,LIPITOR® (atorvastatin), LESCOL® (fluvastatin), lovastatin, LIVALO®(pitavastatin), PRAVACHOL® (pravastatin), CRESTOR® (rosuvastatincalcium), and ZOCOR® (simvastatin)); bile acid sequestrants (e.g.,PREVALITE® (cholestyramine), WELCHOL® (colesevelam), and COLESTID®(colestipol)); PCSK9 Inhibitors (e.g., PRALUENT® (alirocumab) andREPATHA® (evolocumab); niacin (e.g., niaspan and niacor); fibrates(e.g., fenofibrate and LOPID® (gemfibrozil)); and ATP Citrate Lyase(ACL) Inhibitors (e.g., NEXLETOL® (bempedoic)). In some embodiments, thetherapeutic agent that treats or inhibits hypercholesterolemia include,but are not limited to: statins (e.g., atorvastatin, fluvastatin,lovastatin, pitavastatin, pravastatin, rosuvastatin calcium, andsimvastatin); bile acid sequestrants (e.g., cholestyramine, colesevelam,and colestipol); PCSK9 Inhibitors (e.g., alirocumab and evolocumab;niacin (e.g., niaspan and niacor); fibrates (e.g., fenofibrate andgemfibrozil); and ACL Inhibitors (e.g., bempedoic). In some embodiments,the therapeutic agent that treats or inhibits hypercholesterolemia isalirocumab or evolocumab. In some embodiments, the therapeutic agentthat treats or inhibits hypercholesterolemia is alirocumab. In someembodiments, the therapeutic agent that treats or inhibitshypercholesterolemia is evolocumab.

Examples of therapeutic agents that treat or inhibit elevated liverenzymes (such as, for example, ALT and/or AST) include, but are notlimited to, coffee, folic acid, potassium, vitamin B6, a statin, andfiber, or any combination thereof.

Examples of therapeutic agents that treat or inhibit NASH include, butare not limited to, OCALIVA® (obeticholic acid), Pioglitazone or otherglitazones, Selonsertib, Elafibranor, Cenicriviroc, GR_MD_02, MGL_3196,IMM124E, arachidyl amido cholanoic acid (ARAMCHOL™), GS0976, Emricasan,Volixibat, NGM282, GS9674, Tropifexor, MN_001, LMB763, BI_1467335,MSDC_0602, PF_05221304, DF102, Saroglitazar, BMS986036, Lanifibranor,Semaglutide, Nitazoxanide, GRI_0621, EYP001, VK2809, Nalmefene, LIK066,MT_3995, Elobixibat, Namodenoson, Foralumab, SAR425899, Sotagliflozin,EDP_305, Isosabutate, Gemcabene, TERN_101, KBP_042, PF_06865571, DUR928,PF_06835919, NGM313, BMS_986171, Namacizumab, CER_209, ND_L02_s0201,RTU_1096, DRX_065, IONIS_DGAT2Rx, INT_767, NC_001, Seladepar, PXL770,TERN_201, NV556, AZD2693, SP_1373, VK0214, Hepastem, TGFTX4, RLBN1127,GKT_137831, RYI_018, CB4209-CB4211, and JH_0920.

In some embodiments, the therapeutic agent that treats or metabolicdisorders is a melanocortin 4 receptor (MC4R) agonist. In someembodiments, the MC4R agonist comprises a protein, a peptide, a nucleicacid molecule, or a small molecule. In some embodiments, the protein isa peptide analog of MC4R. In some embodiments, the peptide issetmelanotide. In some embodiments, the therapeutic agent that treats orinhibits type 2 diabetes and/or reduces BMI is a combination ofsetmelanotide and one or more of sibutramine, orlistat, phentermine,lorcaserin, naltrexone, liraglutide, diethylpropion, bupropion,metformin, pramlintide, topiramate, and zonisamide. In some embodiments,the MC4R agonist is a peptide comprising the amino acid sequenceHis-Phe-Arg-Trp. In some embodiments, the small molecule is1,2,3R,4-tetrahydroisoquinoline-3-carboxylic acid. In some embodiments,the MC4R agonist is ALB-127158(a).

Examples of therapeutic agents that treat or inhibit cardiomyopathyinclude, but are not limited to: 1) blood pressure lowering agents, suchas ACE inhibitors, angiotensin II receptor blockers, beta blockers, andcalcium channel blockers; 2) agents that slow heart rate, such as betablockers, calcium channel blockers, and digoxin; 3) agents that keep theheart beating with a normal rhythm, such as antiarrhythmics; 4) agentsthat balance electrolytes, such as aldosterone blockers; 5) agents thatremove excess fluid and sodium from the body, such as diuretics; 6)agents that prevent blood clots from forming, such as anticoagulants orblood thinners; and 7) agents that reduce inflammation, such ascorticosteroids.

Examples of therapeutic agents that treat or inhibit heart failureinclude, but are not limited to: ACE inhibitors, angiotensin-2 receptorblockers, beta blockers, mineralocorticoid receptor antagonists,diuretics, ivabradine, sacubitril valsartan, hydralazine with nitrate,and digoxin.

Examples of therapeutic agents that treat or inhibit high blood pressureinclude, but are not limited to: diuretics (such as, chlorthalidone,chlorothiazide, hydrochlorothiazide, indapamide, and metolazone),beta-blockers (such as acebutolol, atenolol, betaxolol, bisoprololfumarate, carteolol hydrochloride, metoprolol tartrate, metoprololsuccinate, nadolol, etc.), ACE inhibitors (such as benazeprilhydrochloride, captopril, enalapril maleate, fosinopril sodium,lisinopril, moexipril, perindopril, quinapril hydrochloride, ramipril,and trandolapril), angiotensin II receptor blockers (such ascandesartan, eprosartan mesylate, irbesartan, losartan potassium,telmisartan, and valsartan), calcium channel blockers (such asamlodipine besylate, bepridil, diltiazem hydrochloride, felodipine,isradipine, nicardipine, nifedipine, nisoldipine, and verapamilhydrochloride), alpha blockers (such as doxazocin mesylate, prazosinhydrochloride, and terazosin hydrochloride), Alpha-2 Receptor Agonists(such as methyldopa), combined alpha and beta-blockers (such ascarvedilol and labetalol hydrochloride), central agonists (such as alphamethyldopa, clonidine hydrochloride, guanabenz acetate, and guanfacinehydrochloride), peripheral adrenergic inhibitors (such as guanadrel,guanethidine monosulfate, and reserpine), and vasodilators (such ashydralazine hydrochloride and minoxidil).

In some embodiments, the dose of the therapeutic agents that treat orinhibit metabolic disorders and/or cardiovascular diseases can bereduced by about 10%, by about 20%, by about 30%, by about 40%, by about50%, by about 60%, by about 70%, by about 80%, or by about 90% forsubjects that are heterozygous for an INHBE predicted loss-of-functionvariant (i.e., a lower than the standard dosage amount) compared tosubjects that are INHBE reference (who may receive a standard dosageamount). In some embodiments, the dose of the therapeutic agents thattreat or inhibit metabolic disorders and/or cardiovascular diseases canbe reduced by about 10%, by about 20%, by about 30%, by about 40%, or byabout 50%. In addition, the subjects that are heterozygous for an INHBEpredicted loss-of-function variant can be administered less frequentlycompared to subjects that are INHBE reference.

In some embodiments, the dose of the therapeutic agents that treat or ametabolic disorder and/or a cardiovascular disease can be reduced byabout 10%, by about 20%, by about 30%, by about 40%, by about 50%, forsubjects that are homozygous for a predicted loss-of-function variantINHBE nucleic acid molecule compared to subjects that are heterozygousfor a predicted loss-of-function variant INHBE nucleic acid molecule. Insome embodiments, the dose of the therapeutic agents that treat orinhibit a metabolic disorder and/or a cardiovascular disease can bereduced by about 10%, by about 20%, by about 30%, by about 40%, or byabout 50%. In addition, the dose of therapeutic agents that treat orinhibit metabolic disorder and/or a cardiovascular disease in subjectsthat are homozygous for a predicted loss-of-function variant INHBEnucleic acid molecule can be administered less frequently compared tosubjects that are heterozygous for a predicted loss-of-function variantINHBE nucleic acid molecule.

Administration of the therapeutic agents that treat or inhibit metabolicdisorders and/or cardiovascular diseases and/or INHBE inhibitors can berepeated, for example, after one day, two days, three days, five days,one week, two weeks, three weeks, one month, five weeks, six weeks,seven weeks, eight weeks, two months, or three months. The repeatedadministration can be at the same dose or at a different dose. Theadministration can be repeated once, twice, three times, four times,five times, six times, seven times, eight times, nine times, ten times,or more. For example, according to certain dosage regimens a subject canreceive therapy for a prolonged period of time such as, for example, 6months, 1 year, or more.

Administration of the therapeutic agents that treat or inhibit metabolicdisorders and/or cardiovascular diseases and/or INHBE inhibitors canoccur by any suitable route including, but not limited to, parenteral,intravenous, oral, subcutaneous, intra-arterial, intracranial,intrathecal, intraperitoneal, topical, intranasal, or intramuscular.Pharmaceutical compositions for administration are desirably sterile andsubstantially isotonic and manufactured under GMP conditions.Pharmaceutical compositions can be provided in unit dosage form (i.e.,the dosage for a single administration). Pharmaceutical compositions canbe formulated using one or more physiologically and pharmaceuticallyacceptable carriers, diluents, excipients or auxiliaries. Theformulation depends on the route of administration chosen. The term“pharmaceutically acceptable” means that the carrier, diluent,excipient, or auxiliary is compatible with the other ingredients of theformulation and not substantially deleterious to the recipient thereof.

The terms “treat”, “treating”, and “treatment” and “prevent”,“preventing”, and “prevention” as used herein, refer to eliciting thedesired biological response, such as a therapeutic and prophylacticeffect, respectively. In some embodiments, a therapeutic effectcomprises one or more of a decrease/reduction in metabolic disordersand/or cardiovascular diseases, a decrease/reduction in the severity ofmetabolic disorders and/or cardiovascular diseases (such as, forexample, a reduction or inhibition of development or metabolic disordersand/or cardiovascular diseases), a decrease/reduction in symptoms andmetabolic disorder-related effects and/or cardiovascular disease-relatedeffects, delaying the onset of symptoms and metabolic disorder-relatedeffects and/or cardiovascular disease-related effects, reducing theseverity of symptoms of metabolic disorder-related effects and/orcardiovascular disease-related effects, reducing the number of symptomsand metabolic disorder-related effects and/or cardiovasculardisease-related effects, reducing the latency of symptoms and metabolicdisorder-related effects and/or cardiovascular disease-related effects,an amelioration of symptoms and metabolic disorder-related effectsand/or cardiovascular disease-related effects, reducing secondarysymptoms, reducing secondary infections, preventing relapse to metabolicdisorders and/or cardiovascular diseases, decreasing the number orfrequency of relapse episodes, increasing latency between symptomaticepisodes, increasing time to sustained progression, speeding recovery,or increasing efficacy of or decreasing resistance to alternativetherapeutics, and/or an increased survival time of the affected hostanimal, following administration of the agent or composition comprisingthe agent. A prophylactic effect may comprise a complete or partialavoidance/inhibition or a delay of metabolic disorders and/orcardiovascular disease development/progression (such as, for example, acomplete or partial avoidance/inhibition or a delay), and an increasedsurvival time of the affected host animal, following administration of atherapeutic protocol. Treatment of metabolic disorders encompasses thetreatment of subjects already diagnosed as having any form of metabolicdisorders and/or cardiovascular diseases at any clinical stage ormanifestation, the delay of the onset or evolution or aggravation ordeterioration of the symptoms or signs of metabolic disorders and/orcardiovascular diseases, and/or preventing and/or reducing the severityof metabolic disorders and/or cardiovascular diseases.

The present disclosure also provides methods of identifying a subjecthaving an increased risk for developing a metabolic disorder. In someembodiments, the method comprises determining or having determined in abiological sample obtained from the subject the presence or absence ofan INHBE variant nucleic acid molecule (such as a genomic nucleic acidmolecule, mRNA molecule, and/or cDNA molecule) encoding an INHBEpredicted loss-of-function polypeptide. When the subject lacks an INHBEvariant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide (i.e., the subject is genotypicallycategorized as an INHBE reference), then the subject has an increasedrisk for developing a metabolic disorder. When the subject has an INHBEvariant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide (i.e., the subject is heterozygous orhomozygous for an INHBE variant nucleic acid molecule encoding an INHBEpredicted loss-of-function polypeptide), then the subject has adecreased risk for developing a metabolic disorder. In some embodiments,liver expression quantitative trait loci (eQTL) can be analyzed.

The present disclosure also provides methods of identifying a subjecthaving an increased risk for developing a cardiovascular disease. Insome embodiments, the method comprises determining or having determinedin a biological sample obtained from the subject the presence or absenceof an INHBE variant nucleic acid molecule (such as a genomic nucleicacid molecule, mRNA molecule, and/or cDNA molecule) encoding an INHBEpredicted loss-of-function polypeptide. When the subject lacks an INHBEvariant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide (i.e., the subject is genotypicallycategorized as an INHBE reference), then the subject has an increasedrisk for developing a cardiovascular disease. When the subject has anINHBE variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide (i.e., the subject is heterozygous orhomozygous for an INHBE variant nucleic acid molecule encoding an INHBEpredicted loss-of-function polypeptide), then the subject has adecreased risk for developing a cardiovascular disease. In someembodiments, liver expression quantitative trait loci (eQTL) can beanalyzed.

Having a single copy of an INHBE variant nucleic acid molecule encodingan INHBE predicted loss-of-function polypeptide is more protective of asubject from developing a metabolic disorder and/or a cardiovasculardisease than having no copies of an INHBE variant nucleic acid moleculeencoding an INHBE predicted loss-of-function polypeptide. Withoutintending to be limited to any particular theory or mechanism of action,it is believed that a single copy of an INHBE variant nucleic acidmolecule (i.e., heterozygous for an INHBE variant nucleic acid molecule)is protective of a subject from developing a metabolic disorder and/or acardiovascular disease, and it is also believed that having two copiesof an INHBE variant nucleic acid molecule (i.e., homozygous for an INHBEvariant nucleic acid molecule) may be more protective of a subject fromdeveloping a metabolic disorder and/or a cardiovascular disease,relative to a subject with a single copy. Thus, in some embodiments, asingle copy of an INHBE variant nucleic acid molecule may not becompletely protective, but instead, may be partially or incompletelyprotective of a subject from developing a metabolic disorder and/or acardiovascular disease. While not desiring to be bound by any particulartheory, there may be additional factors or molecules involved in thedevelopment of metabolic disorders and/or cardiovascular diseases thatare still present in a subject having a single copy of an INHBE variantnucleic acid molecule, thus resulting in less than complete protectionfrom the development of metabolic disorders and/or cardiovasculardiseases.

Determining whether a subject has an INHBE variant nucleic acid moleculeencoding an INHBE predicted loss-of-function polypeptide in a biologicalsample from a subject and/or determining whether a subject has an INHBEvariant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide can be carried out by any of the methodsdescribed herein. In some embodiments, these methods can be carried outin vitro. In some embodiments, these methods can be carried out in situ.In some embodiments, these methods can be carried out in vivo. In any ofthese embodiments, the nucleic acid molecule can be present within acell obtained from the subject.

In some embodiments, when a subject is identified as having an increasedrisk of developing a metabolic disorder, the subject is further treatedwith a therapeutic agent that treats or inhibits metabolic disordersand/or an INHBE inhibitor, as described herein. For example, when thesubject is INHBE reference, and therefore has an increased risk fordeveloping a metabolic disorder, the subject is administered an INHBEinhibitor. In some embodiments, such a subject is also administered atherapeutic agent that treats or inhibits metabolic disorders. In someembodiments, when the subject is heterozygous for an INHBE variantnucleic acid molecule encoding an INHBE predicted loss-of-functionpolypeptide, the subject is administered the therapeutic agent thattreats or inhibits metabolic disorders in a dosage amount that is thesame as or lower than a standard dosage amount, and is also administeredan INHBE inhibitor. In some embodiments, such a subject is alsoadministered a therapeutic agent that treats or inhibits metabolicdisorders. In some embodiments, when the subject is homozygous for anINHBE variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide, the subject is administered thetherapeutic agent that treats or inhibits metabolic disorders in adosage amount that is the same as or lower than a standard dosageamount. In some embodiments, the subject is INHBE reference. In someembodiments, the subject is heterozygous for an INHBE variant nucleicacid molecule encoding an INHBE predicted loss-of-function polypeptide.In some embodiments, the subject is homozygous for an INHBE variantnucleic acid molecule encoding an INHBE predicted loss-of-functionpolypeptide.

In some embodiments, when a subject is identified as having an increasedrisk of developing a cardiovascular disease, the subject is furthertreated with a therapeutic agent that treats or inhibits cardiovasculardiseases and/or an INHBE inhibitor, as described herein. For example,when the subject is INHBE reference, and therefore has an increased riskfor developing a cardiovascular disease, the subject is administered anINHBE inhibitor. In some embodiments, such a subject is alsoadministered a therapeutic agent that treats or inhibits cardiovasculardiseases. In some embodiments, when the subject is heterozygous for anINHBE variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide, the subject is administered thetherapeutic agent that treats or inhibits cardiovascular diseases in adosage amount that is the same as or lower than a standard dosageamount, and is also administered an INHBE inhibitor. In someembodiments, such a subject is also administered a therapeutic agentthat treats or inhibits cardiovascular diseases. In some embodiments,when the subject is homozygous for an INHBE variant nucleic acidmolecule encoding an INHBE predicted loss-of-function polypeptide, thesubject is administered the therapeutic agent that treats or inhibitscardiovascular diseases in a dosage amount that is the same as or lowerthan a standard dosage amount. In some embodiments, the subject is INHBEreference. In some embodiments, the subject is heterozygous for an INHBEvariant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide. In some embodiments, the subject ishomozygous for an INHBE variant nucleic acid molecule encoding an INHBEpredicted loss-of-function polypeptide.

In some embodiments, any of the methods described herein can furthercomprise determining the subject's gene burden of having an INHBEvariant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide, and/or an INHBE predicted loss-of-functionvariant polypeptide associated with a decreased risk of developing ametabolic disorder and/or a cardiovascular disease. The gene burden isthe aggregate of all variants in the INHBE gene, which can be carriedout in an association analysis with metabolic disorders and/orcardiovascular diseases. In some embodiments, the subject is homozygousfor one or more INHBE variant nucleic acid molecules encoding an INHBEpredicted loss-of-function polypeptide associated with a decreased riskof developing a metabolic disorder and/or a cardiovascular disease. Insome embodiments, the subject is heterozygous for one or more INHBEvariant nucleic acid molecules encoding an INHBE predictedloss-of-function polypeptide associated with a decreased risk ofdeveloping a metabolic disorder and/or a cardiovascular disease. Theresult of the association analysis suggests that INHBE variant nucleicacid molecules encoding an INHBE predicted loss-of-function polypeptideare associated with decreased risk of developing a metabolic disorderand/or a cardiovascular disease. When the subject has a lower geneburden, the subject is at a higher risk of developing a metabolicdisorder and/or a cardiovascular disease and the subject is administeredor continued to be administered the therapeutic agent that treats,prevents, or inhibits a metabolic disorder and/or a cardiovasculardisease in a standard dosage amount, and/or an INHBE inhibitor. When thesubject has a greater gene burden, the subject is at a lower risk ofdeveloping a metabolic disorder and/or a cardiovascular disease and thesubject is administered or continued to be administered the therapeuticagent that treats, prevents, or inhibits a metabolic disorder and/or acardiovascular disease in an amount that is the same as or less than thestandard dosage amount. The greater the gene burden, the lower the riskof developing a metabolic disorder and/or a cardiovascular disease.

In some embodiments, the subject's gene burden of having any one or moreINHBE variant nucleic acid molecules encoding an INHBE predictedloss-of-function polypeptide represents a weighted sum of a plurality ofany of the INHBE variant nucleic acid molecules encoding an INHBEpredicted loss-of-function polypeptide. In some embodiments, the geneburden is calculated using at least about 2, at least about 3, at leastabout 4, at least about 5, at least about 10, at least about 20, atleast about 30, at least about 40, at least about 50, at least about 60,at least about 70, at least about 80, at least about 100, at least about120, at least about 150, at least about 200, at least about 250, atleast about 300, at least about 400, at least about 500, at least about1,000, at least about 10,000, at least about 100,000, or at least aboutor more than 1,000,000 genetic variants present in or around (up to 10Mb) the INHBE gene where the gene burden is the number of allelesmultiplied by the association estimate with a metabolic disorder orrelated outcome for each allele (e.g., a weighted burden score). Thiscan include any genetic variants, regardless of their genomicannotation, in proximity to the INHBE gene (up to 10 Mb around the gene)that show a non-zero association with a metabolic disorder-relatedtraits and/or a cardiovascular disease-related traits in a geneticassociation analysis. In some embodiments, when the subject has a geneburden above a desired threshold score, the subject has a decreased riskof developing a metabolic disorder and/or a cardiovascular disease. Insome embodiments, when the subject has a gene burden below a desiredthreshold score, the subject has an increased risk of developing ametabolic disorder and/or a cardiovascular disease.

In some embodiments, the gene burden may be divided into quintiles,e.g., top quintile, intermediate quintile, and bottom quintile, whereinthe top quintile of the gene burden corresponds to the lowest risk groupand the bottom quintile of the gene burden corresponds to the highestrisk group. In some embodiments, a subject having a greater gene burdencomprises the highest weighted gene burdens, including, but not limitedto the top 10%, top 20%, top 30%, top 40%, or top 50% of gene burdensfrom a subject population. In some embodiments, the genetic variantscomprise the genetic variants having association with a metabolicdisorder and/or a cardiovascular disease in the top 10%, top 20%, top30%, top 40%, or top 50% of p-value range for the association. In someembodiments, each of the identified genetic variants comprise thegenetic variants having association with a metabolic disorder and/or acardiovascular disease with p-value of no more than about 10⁻², about10⁻³, about 10⁻⁴, about 10⁻⁵, about 10⁻⁶, about 10⁻⁷, about 10⁻⁸, about10⁻⁹, about 10⁻¹⁰, about 10⁻¹¹, about 10⁻¹², about 10⁻¹³, about 10⁻¹⁴,about or 10⁻¹⁵. In some embodiments, the identified genetic variantscomprise the genetic variants having association with a metabolicdisorder and/or a cardiovascular disease with p-value of less than5×10⁻⁸. In some embodiments, the identified genetic variants comprisegenetic variants having association with a metabolic disorder and/or acardiovascular disease in high-risk subjects as compared to the rest ofthe reference population with odds ratio (OR) about 1.5 or greater,about 1.75 or greater, about 2.0 or greater, or about 2.25 or greaterfor the top 20% of the distribution; or about 1.5 or greater, about 1.75or greater, about 2.0 or greater, about 2.25 or greater, about 2.5 orgreater, or about 2.75 or greater. In some embodiments, the odds ratio(OR) may range from about 1.0 to about 1.5, from about 1.5 to about 2.0,from about 2.0 to about 2.5, from about 2.5 to about 3.0, from about 3.0to about 3.5, from about 3.5 to about 4.0, from about 4.0 to about 4.5,from about 4.5 to about 5.0, from about 5.0 to about 5.5, from about 5.5to about 6.0, from about 6.0 to about 6.5, from about 6.5 to about 7.0,or greater than 7.0. In some embodiments, high-risk subjects comprisesubjects having gene burdens in the bottom decile, quintile, or tertilein a reference population. The threshold of the gene burden isdetermined on the basis of the nature of the intended practicalapplication and the risk difference that would be considered meaningfulfor that practical application.

In some embodiments, when a subject is identified as having an increasedrisk of developing a metabolic disorder, the subject is furtheradministered a therapeutic agent that treats, prevents, or inhibits ametabolic disorder, and/or an INHBE inhibitor, as described herein. Forexample, when the subject is INHBE reference, and therefore has anincreased risk of developing a metabolic disorder, the subject isadministered an INHBE inhibitor. In some embodiments, such a subject isalso administered a therapeutic agent that treats, prevents, or inhibitsa metabolic disorder. In some embodiments, when the subject isheterozygous for an INHBE variant nucleic acid molecule encoding anINHBE predicted loss-of-function polypeptide, the subject isadministered the therapeutic agent that treats, prevents, or inhibits ametabolic disorder in a dosage amount that is the same as or less than astandard dosage amount, and is also administered an INHBE inhibitor. Insome embodiments, the subject is INHBE reference. In some embodiments,the subject is heterozygous for an INHBE variant nucleic acid moleculeencoding an INHBE predicted loss-of-function polypeptide. Furthermore,when the subject has a lower gene burden for having an INHBE variantnucleic acid molecule encoding an INHBE predicted loss-of-functionpolypeptide, and therefore has an increased risk of developing ametabolic disorder, the subject is administered a therapeutic agent thattreats, prevents, or inhibits a metabolic disorder. In some embodiments,when the subject has a lower gene burden for having an INHBE variantnucleic acid molecule encoding an INHBE predicted loss-of-functionpolypeptide, the subject is administered the therapeutic agent thattreats, prevents, or inhibits a metabolic disorder in a dosage amountthat is the same as or greater than the standard dosage amountadministered to a subject who has a greater gene burden for having anINHBE variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide.

In some embodiments, when a subject is identified as having an increasedrisk of developing a cardiovascular disease, the subject is furtheradministered a therapeutic agent that treats, prevents, or inhibits acardiovascular disease, and/or an INHBE inhibitor, as described herein.For example, when the subject is INHBE reference, and therefore has anincreased risk of developing a cardiovascular disease, the subject isadministered an INHBE inhibitor. In some embodiments, such a subject isalso administered a therapeutic agent that treats, prevents, or inhibitsa cardiovascular disease. In some embodiments, when the subject isheterozygous for an INHBE variant nucleic acid molecule encoding anINHBE predicted loss-of-function polypeptide, the subject isadministered the therapeutic agent that treats, prevents, or inhibits acardiovascular disease in a dosage amount that is the same as or lessthan a standard dosage amount, and is also administered an INHBEinhibitor. In some embodiments, the subject is INHBE reference. In someembodiments, the subject is heterozygous for an INHBE variant nucleicacid molecule encoding an INHBE predicted loss-of-function polypeptide.Furthermore, when the subject has a lower gene burden for having anINHBE variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide, and therefore has an increased risk ofdeveloping a cardiovascular disease, the subject is administered atherapeutic agent that treats, prevents, or inhibits a cardiovasculardisease. In some embodiments, when the subject has a lower gene burdenfor having an INHBE variant nucleic acid molecule encoding an INHBEpredicted loss-of-function polypeptide, the subject is administered thetherapeutic agent that treats, prevents, or inhibits a cardiovasculardisease in a dosage amount that is the same as or greater than thestandard dosage amount administered to a subject who has a greater geneburden for having an INHBE variant nucleic acid molecule encoding anINHBE predicted loss-of-function polypeptide.

The present disclosure also provides methods of diagnosing a metabolicdisorder in a subject. The methods comprise determining or havingdetermined whether the subject has any one or more of the INHBE variantnucleic acid molecules or polypeptides produced therefrom describedherein. When the subject is INHBE reference, and has one or moresymptoms of a metabolic disorder, the subject is diagnosed as having ametabolic disorder. In some embodiments, the subject is homozygous for areference INHBE nucleic acid molecule. In some embodiments, the subjectis homozygous or heterozygous for an INHBE variant nucleic acid moleculeencoding a predicted loss-of-function INHBE polypeptide. In someembodiments, when a subject is identified as having metabolic disorder(such as having one or more symptoms of metabolic disorder and beinghomozygous or heterozygous for an INHBE variant nucleic acid moleculeencoding a predicted loss-of-function INHBE polypeptide), the subject isfurther treated with a therapeutic agent that treats or inhibits themetabolic disorder, such as any of those described herein.

The present disclosure also provides methods of diagnosing acardiovascular disease in a subject. The methods comprise determining orhaving determined whether the subject has any one or more of the INHBEvariant nucleic acid molecules or polypeptides produced therefromdescribed herein. When the subject is INHBE reference, and has one ormore symptoms of a cardiovascular disease, the subject is diagnosed ashaving a cardiovascular disease. In some embodiments, the subject ishomozygous for a reference INHBE nucleic acid molecule. In someembodiments, the subject is homozygous or heterozygous for an INHBEvariant nucleic acid molecule encoding a predicted loss-of-functionINHBE polypeptide. In some embodiments, when a subject is identified ashaving cardiovascular disease (such as having one or more symptoms ofcardiovascular disease and being homozygous or heterozygous for an INHBEvariant nucleic acid molecule encoding a predicted loss-of-functionINHBE polypeptide), the subject is further treated with a therapeuticagent that treats or inhibits the cardiovascular disease, such as any ofthose described herein.

The present disclosure also provides methods of identifying a subjecthaving an increased risk for developing a metabolic disorder, whereinthe method comprises determining or having determined in a biologicalsample obtained from the subject the presence or absence of an INHBEpredicted loss-of-function polypeptide. In some embodiments, the methodis a blood based quantitative assay, such as a somalogic assay toquantify inhibin E.

The present disclosure also provides methods of identifying a subjecthaving an increased risk for developing a cardiovascular disease,wherein the method comprises determining or having determined in abiological sample obtained from the subject the presence or absence ofan INHBE predicted loss-of-function polypeptide. In some embodiments,the method is a blood based quantitative assay, such as a somalogicassay to quantify inhibin E.

The presence of INHBE polypeptides in suitable fluid samples, such asblood, plasma, and/or serum, can be determined by detecting the INHBEpolypeptide using numerous methods for measuring INHBE or INHBEactivity. For example, INHBE polypeptide can be detected by immunoassaysusing antibodies specific for INHBE. The antibody being capable ofbinding selectively to an INHBE polypeptide and/or CEA. The antibody canbe used, for example, in Western blots of one- or two-dimensional gels,in high throughput methods such as enzyme linked immunoassay and/or indot blot (Antibody Sandwich) assays of total cellular protein, orpartially purified protein. In some embodiments, the concentration ofINHBE in a suitable fluid is measured by an enzyme-linked immunosorbentassay (ELISA). In one example of the assay, a serum sample is diluted400-fold and applied to a plate to which INHBE polypeptide antibodiesfrom one animal origin (primary antibody) are attached. If enough INHBEis present in the serum, the INHBE may bind to these INHBE antibodies.The plate is then washed to remove all other components of the serum. Aspecially prepared “secondary antibody”, such as from an animal origindifferent from that of the primary antibody, an antibody that binds tothe primary antibody—is then applied to the plate, followed by anotherwash. This secondary antibody is chemically linked in advance to, forexample, an enzyme. Thus, the plate will contain enzyme in proportion tothe amount of secondary antibody bound to the plate. A substrate for theenzyme is applied, and catalysis by the enzyme leads to a change incolor or fluorescence. Samples that generate a signal that is strongerthan the known healthy sample are “positive”. Those that generate weakersignal than the known healthy sample are “negative.”

Alternately, the concentration of INHBE polypeptide in a suitable fluidcan be determined by detecting the INHBE polypeptide using spectrometricmethods, such as LC-MS/MS mass spectrometer, GCMS mass spectrometer, SDSPAGE methods later quantified with densitometry or mass spectrometrymethods or any similar methods of quantifying proteins. Additionalmethods of quantifying polypeptide levels include, but are not limitedto, HPLC (high performance liquid chromatography), SEC (size exclusionchromatography), modified Lowry assay, spectrophotometry, SEC-MALLS(size exclusion chromatography/multi-angle laser light scattering), andNMR (nuclear magnetic resonance).

Aptamers specific for INHBE polypeptides can also be used. A suitableaptamer is capable of binding selectively an INHBE polypeptide formeasuring blood, plasma or serum concentration of INHBE polypeptide, orfor detecting the presence of a variant INHBE. An INHBE polypeptideproduced recombinantly or by chemical synthesis, and fragments or otherderivatives or analogs thereof, including fusion proteins, may be usedas an immunogen to generate aptamers that recognize the INHBEpolypeptide. The term “aptamer” refers to a non-naturally occurringoligonucleotide chain or peptide molecule that has a specific action ona target compound (such as a specific epitope, therapeutic drug markeror surrogate marker). A specific action includes, but is not limited to,binding of the target compound, catalytically changing the targetcompound, and/or reacting with the target compound in a way thatmodifies/alters the target compound or the functional activity of thetarget compound. Aptamers can be engineered through repeated rounds ofin vitro selection or SELEX™ (systematic evolution of ligands byexponential enrichment) to bind to various molecular targets such assmall molecules. Methods for production/synthesis are described in, forexample: Ellington et al., Nature, 1990, 346, 818-822; and Tuerk et al.,Science, 1990, 249, 505-510. The “SELEX™” methodology involves thecombination of selected nucleic acid ligands, which interact with aspecific epitope in a desired action, for example binding to a protein,with amplification of those selected nucleic acids. Optional iterativecycling of the selection/amplification steps allows selection of one ora small number of nucleic acids, which interact most strongly with thespecific epitope from a pool, which contains a very large number ofnucleic acids. Cycling of the selection/amplification procedure iscontinued until a selected goal is achieved. The SELEX methodology isdescribed in the following U.S. Pat. Nos. 5,475,096 and 5,270,163.

The present disclosure also provides methods of identifying a subjecthaving a disease, such as a metabolic disorder, who may responddifferentially to treatment with an INHBE inhibitor or other therapeuticagent affecting fat distribution. In some embodiments, the methodcomprises determining or having determined in a biological sample(liver, plasma, serum, and/or whole blood) obtained from the subject thepresence or absence of an INHBE pLOF or pGOF or that are associated withliver expression of INHBE or measurement of INHBE in circulation orexpression in liver. When the subject lacks such an INHBE variant (i.e.,the subject is genotypically categorized as an INHBE reference), thenthe subject has an increased risk for developing a metabolic disorderand may be amenable to treatment with an INHBE inhibitor or othertherapeutic agent affecting fat distribution. When the subject has suchan INHBE variant nucleic acid molecule (i.e., the subject isheterozygous for an INHBE pLOF/pGOF or homozygous for an INHBEpLOF/pGOF), then the subject has a decreased risk for developing ametabolic disorder.

The present disclosure also provides methods of detecting the presenceor absence of an INHBE variant nucleic acid molecule (genomic, mRNA, orcDNA) encoding a predicted loss-of-function INHBE polypeptide in abiological sample from a subject. It is understood that gene sequenceswithin a population and mRNA molecules encoded by such genes can varydue to polymorphisms such as single-nucleotide polymorphisms.

The biological sample can be derived from any cell, tissue, orbiological fluid from the subject. The sample may comprise anyclinically relevant tissue, such as a bone marrow sample, a tumorbiopsy, a fine needle aspirate, or a sample of bodily fluid, such asblood, gingival crevicular fluid, plasma, serum, lymph, ascitic fluid,cystic fluid, or urine. In some cases, the sample comprises a buccalswab. The sample used in the methods disclosed herein will vary based onthe assay format, nature of the detection method, and the tissues,cells, or extracts that are used as the sample. A biological sample canbe processed differently depending on the assay being employed. Forexample, when detecting any predicted loss-of-function variant INHBEnucleic acid molecule, preliminary processing designed to isolate orenrich the sample for the genomic DNA can be employed. A variety oftechniques may be used for this purpose. When detecting the level of anypredicted loss-of-function variant INHBE mRNA, different techniques canbe used enrich the biological sample with mRNA. Various methods todetect the presence or level of an mRNA or the presence of a particularvariant genomic DNA locus can be used.

In some embodiments, detecting an INHBE variant nucleic acid moleculeencoding a predicted loss-of-function INHBE polypeptide in a subjectcomprises assaying or genotyping a biological sample obtained from thesubject to determine whether an INHBE genomic nucleic acid molecule inthe biological sample, and/or an INHBE mRNA molecule in the biologicalsample, and/or an INHBE cDNA molecule produced from an mRNA molecule inthe biological sample, comprises one or more variations that cause aloss-of-function (partial or complete) or are predicted to cause aloss-of-function (partial or complete), such as any of the INHBE variantnucleic acid molecules encoding a predicted loss-of-function INHBEpolypeptide described herein.

In some embodiments, the methods of detecting the presence or absence ofan INHBE variant nucleic acid molecule (such as, for example, a genomicnucleic acid molecule, an mRNA molecule, and/or a cDNA molecule producedfrom an mRNA molecule) in a subject, comprise performing an assay on abiological sample obtained from the subject. The assay determineswhether a nucleic acid molecule in the biological sample comprises aparticular nucleotide sequence.

In some embodiments, the biological sample comprises a cell or celllysate. Such methods can further comprise, for example, obtaining abiological sample from the subject comprising an INHBE genomic nucleicacid molecule or mRNA molecule, and if mRNA, optionally reversetranscribing the mRNA into cDNA. Such assays can comprise, for exampledetermining the identity of these positions of the particular INHBEnucleic acid molecule. In some embodiments, the method is an in vitromethod.

In some embodiments, the determining step, detecting step, or genotypingassay comprises sequencing at least a portion of the nucleotide sequenceof the INHBE genomic nucleic acid molecule, the INHBE mRNA molecule, orthe INHBE cDNA molecule in the biological sample, wherein the sequencedportion comprises one or more variations that cause a loss-of-function(partial or complete) or are predicted to cause a loss-of-function(partial or complete), such as any of the predicted loss-of-functionvariant INHBE nucleic acid molecules described herein.

In some embodiments, the determining step, detecting step, or genotypingassay comprises sequencing at least a portion of the nucleotide sequenceof the INHBE genomic nucleic acid molecule in the biological sample, thenucleotide sequence of the INHBE mRNA molecule in the biological sample,or the nucleotide sequence of the INHBE cDNA molecule produced from theINHBE mRNA in the biological sample. In some embodiments, thedetermining step, detecting step, or genotyping assay comprisessequencing at least a portion of the nucleotide sequence of the INHBEgenomic nucleic acid molecule in the biological sample. In someembodiments, the determining step, detecting step, or genotyping assaycomprises sequencing at least a portion of the nucleotide sequence ofthe INHBE mRNA molecule in the biological sample. In some embodiments,the determining step, detecting step, or genotyping assay comprisessequencing at least a portion of the nucleotide sequence of the INHBEcDNA molecule produced from the INHBE mRNA molecule in the biologicalsample.

In some embodiments, the assay comprises sequencing the entire nucleicacid molecule. In some embodiments, only an INHBE genomic nucleic acidmolecule is analyzed. In some embodiments, only an INHBE mRNA isanalyzed. In some embodiments, only an INHBE cDNA obtained from INHBEmRNA is analyzed.

In some embodiments, the determining step, detecting step, or genotypingassay comprises: a) amplifying at least a portion of the nucleic acidmolecule that encodes the INHBE polypeptide; b) labeling the amplifiednucleic acid molecule with a detectable label; c) contacting the labelednucleic acid molecule with a support comprising an alteration-specificprobe; and d) detecting the detectable label.

In some embodiments, the nucleic acid molecule is mRNA and thedetermining step further comprises reverse-transcribing the mRNA into acDNA prior to the amplifying step.

In some embodiments, the determining step, detecting step, or genotypingassay comprises: contacting the nucleic acid molecule in the biologicalsample with an alteration-specific probe comprising a detectable label,wherein the alteration-specific probe comprises a nucleotide sequencewhich hybridizes under stringent conditions to the nucleotide sequenceof the amplified nucleic acid molecule; and detecting the detectablelabel. Alteration-specific polymerase chain reaction techniques can beused to detect mutations such as SNPs in a nucleic acid sequence.Alteration-specific primers can be used because the DNA polymerase willnot extend when a mismatch with the template is present.

In some embodiments, the nucleic acid molecule in the sample is mRNA andthe mRNA is reverse-transcribed into a cDNA prior to the amplifyingstep. In some embodiments, the nucleic acid molecule is present within acell obtained from the subject.

In some embodiments, the assay comprises contacting the biologicalsample with a primer or probe, such as an alteration-specific primer oralteration-specific probe, that specifically hybridizes to an INHBEvariant nucleic acid molecule (genomic, mRNA, or cDNA) and not thecorresponding INHBE reference sequence under stringent conditions, anddetermining whether hybridization has occurred. In some embodiments, theassay comprises RNA sequencing (RNA-Seq). In some embodiments, theassays also comprise reverse transcribing mRNA into cDNA, such as by thereverse transcriptase polymerase chain reaction (RT-PCR).

In some embodiments, the methods utilize probes and primers ofsufficient nucleotide length to bind to the target nucleotide sequenceand specifically detect and/or identify a polynucleotide comprising anINHBE variant nucleic acid molecule (genomic, mRNA, or cDNA) encoding apredicted loss-of-function INHBE polypeptide. The hybridizationconditions or reaction conditions can be determined by the operator toachieve this result. The nucleotide length may be any length that issufficient for use in a detection method of choice, including any assaydescribed or exemplified herein. Such probes and primers can hybridizespecifically to a target nucleotide sequence under high stringencyhybridization conditions. Probes and primers may have completenucleotide sequence identity of contiguous nucleotides within the targetnucleotide sequence, although probes differing from the targetnucleotide sequence and that retain the ability to specifically detectand/or identify a target nucleotide sequence may be designed byconventional methods. Probes and primers can have about 80%, about 85%,about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about96%, about 97%, about 98%, about 99%, or 100% sequence identity orcomplementarity with the nucleotide sequence of the target nucleic acidmolecule.

Illustrative examples of nucleic acid sequencing techniques include, butare not limited to, chain terminator (Sanger) sequencing and dyeterminator sequencing. Other methods involve nucleic acid hybridizationmethods other than sequencing, including using labeled primers or probesdirected against purified DNA, amplified DNA, and fixed cellpreparations (fluorescence in situ hybridization (FISH)). In somemethods, a target nucleic acid molecule may be amplified prior to orsimultaneous with detection. Illustrative examples of nucleic acidamplification techniques include, but are not limited to, polymerasechain reaction (PCR), ligase chain reaction (LCR), strand displacementamplification (SDA), and nucleic acid sequence based amplification(NASBA). Other methods include, but are not limited to, ligase chainreaction, strand displacement amplification, and thermophilic SDA(tSDA).

In hybridization techniques, stringent conditions can be employed suchthat a probe or primer will specifically hybridize to its target. Insome embodiments, a polynucleotide primer or probe under stringentconditions will hybridize to its target sequence to a detectably greaterdegree than to other non-target sequences, such as, at least 2-fold, atleast 3-fold, at least 4-fold, or more over background, including over10-fold over background. In some embodiments, a polynucleotide primer orprobe under stringent conditions will hybridize to its target nucleotidesequence to a detectably greater degree than to other nucleotidesequences by at least 2-fold. In some embodiments, a polynucleotideprimer or probe under stringent conditions will hybridize to its targetnucleotide sequence to a detectably greater degree than to othernucleotide sequences by at least 3-fold. In some embodiments, apolynucleotide primer or probe under stringent conditions will hybridizeto its target nucleotide sequence to a detectably greater degree than toother nucleotide sequences by at least 4-fold. In some embodiments, apolynucleotide primer or probe under stringent conditions will hybridizeto its target nucleotide sequence to a detectably greater degree than toother nucleotide sequences by over 10-fold over background. Stringentconditions are sequence-dependent and will be different in differentcircumstances.

Appropriate stringency conditions which promote DNA hybridization, forexample, 6× sodium chloride/sodium citrate (SSC) at about 45° C.,followed by a wash of 2×SSC at 50° C., are known or can be found inCurrent Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989),6.3.1-6.3.6. Typically, stringent conditions for hybridization anddetection will be those in which the salt concentration is less thanabout 1.5 M Na⁺ ion, typically about 0.01 to 1.0 M Na⁺ ion concentration(or other salts) at pH 7.0 to 8.3 and the temperature is at least about30° C. for short probes (such as, for example, 10 to 50 nucleotides) andat least about 60° C. for longer probes (such as, for example, greaterthan 50 nucleotides). Stringent conditions may also be achieved with theaddition of destabilizing agents such as formamide. Optionally, washbuffers may comprise about 0.1% to about 1% SDS. Duration ofhybridization is generally less than about 24 hours, usually about 4 toabout 12 hours. The duration of the wash time will be at least a lengthof time sufficient to reach equilibrium.

The present disclosure also provides methods of detecting the presenceof a human INHBE predicted loss-of-function polypeptide comprisingperforming an assay on a sample obtained from a subject to determinewhether an INHBE polypeptide in the subject contains one or morevariations that causes the polypeptide to have a loss-of-function(partial or complete) or predicted loss-of-function (partial orcomplete).

In some embodiments, the detecting step comprises sequencing at least aportion of the polypeptide. In some embodiments, the detecting stepcomprises an immunoassay for detecting the presence of a polypeptide.

In some embodiments, when the subject does not have an INHBE predictedloss-of-function polypeptide, then the subject has an increased risk fordeveloping a metabolic disorder or any of type 2 diabetes,lipodystrophy, liver inflammation, fatty liver disease,hypercholesterolemia, elevated liver enzymes (such as, for example, ALTand/or AST), obesity, high blood pressure, NASH, and/or elevatedtriglyceride level. In some embodiments, when the subject has an INHBEpredicted loss-of-function polypeptide, then the subject has a decreasedrisk for developing a metabolic disorder or any of type 2 diabetes,obesity, lipodystrophy, liver inflammation, fatty liver disease,hypercholesterolemia, elevated liver enzymes (such as, for example, ALTand/or AST), high blood pressure, NASH, and/or elevated triglyceridelevel.

In some embodiments, when the subject does not have an INHBE predictedloss-of-function polypeptide, then the subject has an increased risk fordeveloping a cardiovascular disease or any of cardiomyopathy, heartfailure, and high blood pressure. In some embodiments, when the subjecthas an INHBE predicted loss-of-function polypeptide, then the subjecthas a decreased risk for developing a cardiovascular disease or any ofcardiomyopathy, heart failure, and high blood pressure.

The present disclosure also provides uses of isolated nucleic acidmolecules that hybridize to INHBE variant genomic nucleic acidmolecules, INHBE variant mRNA molecules, and/or INHBE variant cDNAmolecules (such as any of the genomic variant nucleic acid molecules,mRNA variant molecules, and cDNA variant molecules disclosed herein) inany of the methods described herein.

In some embodiments, such isolated nucleic acid molecules comprise orconsist of at least about 5, at least about 8, at least about 10, atleast about 11, at least about 12, at least about 13, at least about 14,at least about 15, at least about 16, at least about 17, at least about18, at least about 19, at least about 20, at least about 21, at leastabout 22, at least about 23, at least about 24, at least about 25, atleast about 30, at least about 35, at least about 40, at least about 45,at least about 50, at least about 55, at least about 60, at least about65, at least about 70, at least about 75, at least about 80, at leastabout 85, at least about 90, at least about 95, at least about 100, atleast about 200, at least about 300, at least about 400, at least about500, at least about 600, at least about 700, at least about 800, atleast about 900, at least about 1000, at least about 2000, at leastabout 3000, at least about 4000, or at least about 5000 nucleotides. Insome embodiments, such isolated nucleic acid molecules comprise orconsist of at least about 5, at least about 8, at least about 10, atleast about 11, at least about 12, at least about 13, at least about 14,at least about 15, at least about 16, at least about 17, at least about18, at least about 19, at least about 20, at least about 21, at leastabout 22, at least about 23, at least about 24, or at least about 25nucleotides. In some embodiments, the isolated nucleic acid moleculescomprise or consist of at least about 18 nucleotides. In someembodiments, the isolated nucleic acid molecules comprise or consists ofat least about 15 nucleotides. In some embodiments, the isolated nucleicacid molecules consist of or comprise from about 10 to about 35, fromabout 10 to about 30, from about 10 to about 25, from about 12 to about30, from about 12 to about 28, from about 12 to about 24, from about 15to about 30, from about 15 to about 25, from about 18 to about 30, fromabout 18 to about 25, from about 18 to about 24, or from about 18 toabout 22 nucleotides. In some embodiments, the isolated nucleic acidmolecules consist of or comprise from about 18 to about 30 nucleotides.In some embodiments, the isolated nucleic acid molecules comprise orconsist of at least about 15 nucleotides to at least about 35nucleotides.

In some embodiments, such isolated nucleic acid molecules hybridize toINHBE variant nucleic acid molecules (such as genomic nucleic acidmolecules, mRNA molecules, and/or cDNA molecules) under stringentconditions. Such nucleic acid molecules can be used, for example, asprobes, primers, alteration-specific probes, or alteration-specificprimers as described or exemplified herein, and include, withoutlimitation primers, probes, antisense RNAs, shRNAs, and siRNAs, each ofwhich is described in more detail elsewhere herein, and can be used inany of the methods described herein.

In some embodiments, the isolated nucleic acid molecules hybridize to atleast about 15 contiguous nucleotides of a nucleic acid molecule that isat least about 70%, at least about 75%, at least about 80%, at leastabout 85%, at least about 90%, at least about 95%, at least about 96%,at least about 97%, at least about 98%, at least about 99%, or 100%identical to INHBE variant genomic nucleic acid molecules, INHBE variantmRNA molecules, and/or INHBE variant cDNA molecules. In someembodiments, the isolated nucleic acid molecules consist of or comprisefrom about 15 to about 100 nucleotides, or from about 15 to about 35nucleotides. In some embodiments, the isolated nucleic acid moleculesconsist of or comprise from about 15 to about 100 nucleotides. In someembodiments, the isolated nucleic acid molecules consist of or comprisefrom about 15 to about 35 nucleotides.

In some embodiments, the alteration-specific probes andalteration-specific primers comprise DNA. In some embodiments, thealteration-specific probes and alteration-specific primers comprise RNA.

In some embodiments, the probes and primers described herein (includingalteration-specific probes and alteration-specific primers) have anucleotide sequence that specifically hybridizes to any of the nucleicacid molecules disclosed herein, or the complement thereof. In someembodiments, the probes and primers specifically hybridize to any of thenucleic acid molecules disclosed herein under stringent conditions.

In some embodiments, the primers, including alteration-specific primers,can be used in second generation sequencing or high throughputsequencing. In some instances, the primers, includingalteration-specific primers, can be modified. In particular, the primerscan comprise various modifications that are used at different steps of,for example, Massive Parallel Signature Sequencing (MPSS), Polonysequencing, and 454 Pyrosequencing. Modified primers can be used atseveral steps of the process, including biotinylated primers in thecloning step and fluorescently labeled primers used at the bead loadingstep and detection step. Polony sequencing is generally performed usinga paired-end tags library wherein each molecule of DNA template is about135 bp in length. Biotinylated primers are used at the bead loading stepand emulsion PCR. Fluorescently labeled degenerate nonameroligonucleotides are used at the detection step. An adaptor can containa 5′-biotin tag for immobilization of the DNA library ontostreptavidin-coated beads.

The probes and primers described herein can be used to detect anucleotide variation within any of the INHBE variant genomic nucleicacid molecules, INHBE variant mRNA molecules, and/or INHBE variant cDNAmolecules disclosed herein. The primers described herein can be used toamplify INHBE variant genomic nucleic acid molecules, INHBE variant mRNAmolecules, or INHBE variant cDNA molecules, or a fragment thereof.

In the context of the disclosure “specifically hybridizes” means thatthe probe or primer (such as, for example, the alteration-specific probeor alteration-specific primer) does not hybridize to a nucleic acidsequence encoding an INHBE reference genomic nucleic acid molecule, anINHBE reference mRNA molecule, and/or an INHBE reference cDNA molecule.

In some embodiments, the probes (such as, for example, analteration-specific probe) comprise a label. In some embodiments, thelabel is a fluorescent label, a radiolabel, or biotin.

The present disclosure also provides supports comprising a substrate towhich any one or more of the probes disclosed herein is attached. Solidsupports are solid-state substrates or supports with which molecules,such as any of the probes disclosed herein, can be associated. A form ofsolid support is an array. Another form of solid support is an arraydetector. An array detector is a solid support to which multipledifferent probes have been coupled in an array, grid, or other organizedpattern. A form for a solid-state substrate is a microtiter dish, suchas a standard 96-well type. In some embodiments, a multiwell glass slidecan be employed that normally contains one array per well.

The nucleotide sequence of an INHBE reference genomic nucleic acidmolecule is set forth in SEQ ID NO:1 (ENST00000266646.3 encompassingchr12:57455307-57458025 in the GRCh38/hg38 human genome assembly).

The nucleotide sequence of an INHBE reference mRNA molecule is set forthin SEQ ID NO:2. The nucleotide sequence of another INHBE reference mRNAmolecule is set forth in SEQ ID NO:3. The nucleotide sequence of anotherINHBE reference mRNA molecule is set forth in SEQ ID NO:4.

The nucleotide sequence of an INHBE reference cDNA molecule is set forthin SEQ ID NO:5. The nucleotide sequence of another INHBE reference cDNAmolecule is set forth in SEQ ID NO:6. The nucleotide sequence of anotherINHBE reference cDNA molecule is set forth in SEQ ID NO:7.

The amino acid sequence of an INHBE reference polypeptide is set forthin SEQ ID NO:8. Referring to SEQ ID NO:8, the INHBE referencepolypeptide is 350 amino acids in length.

The genomic nucleic acid molecules, mRNA molecules, and cDNA moleculescan be from any organism. For example, the genomic nucleic acidmolecules, mRNA molecules, and cDNA molecules can be human or anortholog from another organism, such as a non-human mammal, a rodent, amouse, or a rat. It is understood that gene sequences within apopulation can vary due to polymorphisms such as single-nucleotidepolymorphisms. The examples provided herein are only exemplarysequences. Other sequences are also possible.

The isolated nucleic acid molecules disclosed herein can comprise RNA,DNA, or both RNA and DNA. The isolated nucleic acid molecules can alsobe linked or fused to a heterologous nucleic acid sequence, such as in avector, or a heterologous label. For example, the isolated nucleic acidmolecules disclosed herein can be within a vector or as an exogenousdonor sequence comprising the isolated nucleic acid molecule and aheterologous nucleic acid sequence. The isolated nucleic acid moleculescan also be linked or fused to a heterologous label. The label can bedirectly detectable (such as, for example, fluorophore) or indirectlydetectable (such as, for example, hapten, enzyme, or fluorophorequencher). Such labels can be detectable by spectroscopic,photochemical, biochemical, immunochemical, or chemical means. Suchlabels include, for example, radiolabels, pigments, dyes, chromogens,spin labels, and fluorescent labels. The label can also be, for example,a chemiluminescent substance; a metal-containing substance; or anenzyme, where there occurs an enzyme-dependent secondary generation ofsignal. The term “label” can also refer to a “tag” or hapten that canbind selectively to a conjugated molecule such that the conjugatedmolecule, when added subsequently along with a substrate, is used togenerate a detectable signal. For example, biotin can be used as a tagalong with an avidin or streptavidin conjugate of horseradish peroxidate(HRP) to bind to the tag, and examined using a calorimetric substrate(such as, for example, tetramethylbenzidine (TMB)) or a fluorogenicsubstrate to detect the presence of HRP. Exemplary labels that can beused as tags to facilitate purification include, but are not limited to,myc, HA, FLAG or 3×FLAG, 6×His or polyhistidine,glutathione-S-transferase (GST), maltose binding protein, an epitopetag, or the Fc portion of immunoglobulin. Numerous labels include, forexample, particles, fluorophores, haptens, enzymes and theircalorimetric, fluorogenic and chemiluminescent substrates and otherlabels.

The disclosed nucleic acid molecules can comprise, for example,nucleotides or non-natural or modified nucleotides, such as nucleotideanalogs or nucleotide substitutes. Such nucleotides include a nucleotidethat contains a modified base, sugar, or phosphate group, or thatincorporates a non-natural moiety in its structure. Examples ofnon-natural nucleotides include, but are not limited to,dideoxynucleotides, biotinylated, aminated, deaminated, alkylated,benzylated, and fluorophor-labeled nucleotides.

The nucleic acid molecules disclosed herein can also comprise one ormore nucleotide analogs or substitutions. A nucleotide analog is anucleotide which contains a modification to either the base, sugar, orphosphate moieties. Modifications to the base moiety include, but arenot limited to, natural and synthetic modifications of A, C, G, and T/U,as well as different purine or pyrimidine bases such as, for example,pseudouridine, uracil-5-yl, hypoxanthin-9-yl (I), and2-aminoadenin-9-yl. Modified bases include, but are not limited to,5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine,hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives ofadenine and guanine, 2-propyl and other alkyl derivatives of adenine andguanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouraciland cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine andthymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino,8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines andguanines, 5-halo (such as, for example, 5-bromo), 5-trifluoromethyl andother 5-substituted uracils and cytosines, 7-methylguanine,7-methyladenine, 8-azaguanine, 8-azaadenine, 7-deazaguanine,7-deazaadenine, 3-deazaguanine, and 3-deazaadenine.

Nucleotide analogs can also include modifications of the sugar moiety.Modifications to the sugar moiety include, but are not limited to,natural modifications of the ribose and deoxy ribose as well assynthetic modifications. Sugar modifications include, but are notlimited to, the following modifications at the 2′ position: OH; F; O-,S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; orO-alkyl-O-alkyl, wherein the alkyl, alkenyl, and alkynyl may besubstituted or unsubstituted C₁₋₁₀alkyl or C₂₋₁₀alkenyl, andC₂₋₁₀alkynyl. Exemplary 2′ sugar modifications also include, but are notlimited to, —O[(CH₂)_(n)O]_(m)CH₃, —O(CH₂)_(n)OCH₃, —O(CH₂)_(n)NH₂,—O(CH₂)_(n)CH₃, —O(CH₂)_(n)—ONH₂, and —O(CH₂)_(n)ON[(CH₂)_(n)CH₃)]₂,where n and m are from 1 to about 10. Other modifications at the 2′position include, but are not limited to, C₁₋₁₀alkyl, substituted loweralkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH₃, OCN, Cl, Br,CN, CF₃, OCF₃, SOCH₃, SO₂CH₃, ONO₂, NO₂, N₃, NH₂, heterocycloalkyl,heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl,an RNA cleaving group, a reporter group, an intercalator, a group forimproving the pharmacokinetic properties of an oligonucleotide, or agroup for improving the pharmacodynamic properties of anoligonucleotide, and other substituents having similar properties.Similar modifications may also be made at other positions on the sugar,particularly the 3′ position of the sugar on the 3′ terminal nucleotideor in 2′-5′ linked oligonucleotides and the 5′ position of 5′ terminalnucleotide. Modified sugars can also include those that containmodifications at the bridging ring oxygen, such as CH₂ and S. Nucleotidesugar analogs can also have sugar mimetics, such as cyclobutyl moietiesin place of the pentofuranosyl sugar.

Nucleotide analogs can also be modified at the phosphate moiety.Modified phosphate moieties include, but are not limited to, those thatcan be modified so that the linkage between two nucleotides contains aphosphorothioate, chiral phosphorothioate, phosphorodithioate,phosphotriester, aminoalkylphosphotriester, methyl and other alkylphosphonates including 3′-alkylene phosphonate and chiral phosphonates,phosphinates, phosphoramidates including 3′-amino phosphoramidate andaminoalkylphosphoramidates, thionophosphoramidates,thionoalkylphosphonates, thionoalkylphosphotriesters, andboranophosphates. These phosphate or modified phosphate linkage betweentwo nucleotides can be through a 3′-5′ linkage or a 2′-5′ linkage, andthe linkage can contain inverted polarity such as 3′-5′ to 5′-3′ or2′-5′ to 5′-2′. Various salts, mixed salts, and free acid forms are alsoincluded. Nucleotide substitutes also include peptide nucleic acids(PNAs).

The present disclosure also provides therapeutic agents that treat orinhibit a metabolic disorder for use in the treatment of the metabolicdisorder in a subject having: an INHBE variant genomic nucleic acidmolecule encoding a predicted loss-of-function INHBE polypeptide; anINHBE variant mRNA molecule encoding a predicted loss-of-function INHBEpolypeptide; or an INHBE variant cDNA molecule encoding a predictedloss-of-function INHBE polypeptide.

In some embodiments, the metabolic disorder is type 2 diabetes, and thetherapeutic agent is chosen from metformin, insulin, glyburide,glipizide, glimepiride, repaglinide, nateglinide, thiazolidinediones,rosiglitazone, pioglitazone, sitagliptin, saxagliptin, linagliptin,exenatide, liraglutide, semaglutide, canagliflozin, dapagliflozin, andempagliflozin.

In some embodiments, the metabolic disorder is obesity, and thetherapeutic agent is chosen from orlistat, phentermine, topiramate,bupropion, naltrexone, and liraglutide.

In some embodiments, the metabolic disorder is high blood pressure, andthe therapeutic agent is chosen from chlorthalidone, chlorothiazide,hydrochlorothiazide, indapamide, metolazone, acebutolol, atenolol,betaxolol, bisoprolol fumarate, carteolol hydrochloride, metoprololtartrate, metoprolol succinate, nadolol, benazepril hydrochloride,captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril,perindopril, quinapril hydrochloride, ramipril, trandolapril,candesartan, eprosartan mesylate, irbesartan, losartan potassium,telmisartan, valsartan, amlodipine besylate, bepridil, diltiazemhydrochloride, felodipine, isradipine, nicardipine, nifedipine,nisoldipine, verapamil hydrochloride, doxazosin mesylate, prazosinhydrochloride, terazosin hydrochloride, methyldopa, carvedilol labetalolhydrochloride, alpha methyldopa, clonidine hydrochloride, guanabenzacetate, guanfacine hydrochloride, guanadrel, guanethidine monosulfate,reserpine, hydralazine hydrochloride, and minoxidil.

In some embodiments, the metabolic disorder is elevated triglyceride,and the therapeutic agent is chosen from rosuvastatin, simvastatin,atorvastatin, fenofibrate, gemfibrozil, fenofibric acid, niacin, and anomega-3 fatty acid.

In some embodiments, the metabolic disorder is lipodystrophy, and thetherapeutic agent is chosen from EGRIFTA® (tesamorelin), GLUCOPHAGE®(metformin), SCULPTRA® (poly-L-lactic acid), RADIESSE® (calciumhydroxyapatite), polymethylmethacrylate (e.g., PMMA), ZYDERM® (bovinecollagen), COSMODERM® (human collagen), silicone, and hyaluronic acid.In some embodiments, the therapeutic agent that treats or inhibitslipodystrophy include, but are not limited to: tesamorelin, metformin,poly-L-lactic acid, a calcium hydroxyapatite, polymethylmethacrylate, abovine collagen, a human collagen, silicone, and hyaluronic acid.

In some embodiments, the metabolic disorder is liver inflammation, andthe therapeutic agent is chosen from hepatitis therapeutics andhepatitis vaccines.

In some embodiments, the metabolic disorder is fatty liver diseaseinclude, and the therapeutic agent or procedure is bariatric surgeryand/or dietary intervention.

In some embodiments, the metabolic disorder is hypercholesterolemia, andthe therapeutic agent is chosen from: statins (e.g., LIPITOR®(atorvastatin), LESCOL® (fluvastatin), lovastatin, LIVALO®(pitavastatin), PRAVACHOL® (pravastatin), CRESTOR® (rosuvastatincalcium), and ZOCOR® (simvastatin)); bile acid sequestrants (e.g.,PREVALITE® (cholestyramine), WELCHOL® (colesevelam), and COLESTID®(colestipol)); PCSK9 Inhibitors (e.g., PRALUENT® (alirocumab) andREPATHA® (evolocumab); niacin (e.g., niaspan and niacor); fibrates(e.g., fenofibrate and LOPID® (gemfibrozil)); and ATP Citrate Lyase(ACL) Inhibitors (e.g., NEXLETOL® (bempedoic)). In some embodiments, thetherapeutic agent that treats or inhibits hypercholesterolemia include,but are not limited to: statins (e.g., atorvastatin, fluvastatin,lovastatin, pitavastatin, pravastatin, rosuvastatin calcium, andsimvastatin); bile acid sequestrants (e.g., cholestyramine, colesevelam,and colestipol); PCSK9 Inhibitors (e.g., alirocumab and evolocumab;niacin (e.g., niaspan and niacor); fibrates (e.g., fenofibrate andgemfibrozil); and ACL Inhibitors (e.g., bempedoic). In some embodiments,the therapeutic agent that treats or inhibits hypercholesterolemia isalirocumab or evolocumab. In some embodiments, the therapeutic agentthat treats or inhibits hypercholesterolemia is alirocumab. In someembodiments, the therapeutic agent that treats or inhibitshypercholesterolemia is evolocumab.

In some embodiments, the metabolic disorder is elevated liver enzymes(such as, for example, ALT and/or AST), and the therapeutic agent ischosen from coffee, folic acid, potassium, vitamin B6, a statin, andfiber, or any combination thereof.

In some embodiments, the metabolic disorder is NASH and the therapeuticagent is obeticholic acid, Selonsertib, Elafibranor, Cenicriviroc,GR_MD_02, MGL_3196, IMM124E, arachidyl amido cholanoic acid, GS0976,Emricasan, Volixibat, NGM282, GS9674, Tropifexor, MN_001, LMB763,BI_1467335, MSDC_0602, PF_05221304, DF102, Saroglitazar, BMS986036,Lanifibranor, Semaglutide, Nitazoxanide, GRI_0621, EYP001, VK2809,Nalmefene, LIK066, MT_3995, Elobixibat, Namodenoson, Foralumab,SAR425899, Sotagliflozin, EDP_305, Isosabutate, Gemcabene, TERN_101,KBP_042, PF_06865571, DUR928, PF_06835919, NGM313, BMS_986171,Namacizumab, CER_209, ND_L02_s0201, RTU_1096, DRX_065, ION IS_DGAT2Rx,INT_767, NC_001, Seladepar, PXL770, TERN_201, NV556, AZD2693, SP_1373,VK0214, Hepastem, TGFTX4, RLBN1127, GKT_137831, RYI_018, CB4209-CB4211,and JH_0920.

In some embodiments, the therapeutic agent that treats or inhibits themetabolic disorder is a melanocortin 4 receptor (MC4R) agonist. In someembodiments, the MC4R agonist comprises a protein, a peptide, a nucleicacid molecule, or a small molecule. In some embodiments, the protein isa peptide analog of MC4R. In some embodiments, the peptide issetmelanotide. In some embodiments, the MC4R agonist is a peptidecomprising the amino acid sequence His-Phe-Arg-Trp. In some embodiments,the small molecule is 1,2,3R,4-tetrahydroisoquinoline-3-carboxylic acid.In some embodiments, the MC4R agonist is ALB-127158(a).

The present disclosure also provides therapeutic agents that treat orinhibit a cardiovascular disease for use in the treatment of thecardiovascular disease in a subject having: an INHBE variant genomicnucleic acid molecule encoding a predicted loss-of-function INHBEpolypeptide; an INHBE variant mRNA molecule encoding a predictedloss-of-function INHBE polypeptide; or an INHBE variant cDNA moleculeencoding a predicted loss-of-function INHBE polypeptide.

In some embodiments, the cardiovascular disease is high blood pressure,and the therapeutic agent is chosen from chlorthalidone, chlorothiazide,hydrochlorothiazide, indapamide, metolazone, acebutolol, atenolol,betaxolol, bisoprolol fumarate, carteolol hydrochloride, metoprololtartrate, metoprolol succinate, nadolol, benazepril hydrochloride,captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril,perindopril, quinapril hydrochloride, ramipril, trandolapril,candesartan, eprosartan mesylate, irbesartan, losartan potassium,telmisartan, valsartan, amlodipine besylate, bepridil, diltiazemhydrochloride, felodipine, Isradipine, nicardipine, nifedipine,nisoldipine, verapamil hydrochloride, doxazosin mesylate, prazosinhydrochloride, terazosin hydrochloride, methyldopa, carvedilol labetalolhydrochloride, alpha methyldopa, clonidine hydrochloride, guanabenzacetate, guanfacine hydrochloride, guanadrel, guanethidine monosulfate,reserpine, hydralazine hydrochloride, and minoxidil.

In some embodiments, the cardiovascular disease is cardiomyopathy, andthe therapeutic agent is chosen from: 1) blood pressure lowering agents,such as ACE inhibitors, angiotensin II receptor blockers, beta blockers,and calcium channel blockers; 2) agents that slow heart rate, such asbeta blockers, calcium channel blockers, and digoxin; 3) agents thatkeep the heart beating with a normal rhythm, such as antiarrhythmics; 4)agents that balance electrolytes, such as aldosterone blockers; 5)agents that remove excess fluid and sodium from the body, such asdiuretics; 6) agents that prevent blood clots from forming, such asanticoagulants or blood thinners; and 7) agents that reduceinflammation, such as corticosteroids.

In some embodiments, the cardiovascular disease is heart failure, andthe therapeutic agent is chosen from: an ACE inhibitor, an angiotensin-2receptor blocker, a beta blocker, a mineralocorticoid receptorantagonist, a diuretic, ivabradine, sacubitril valsartan, hydralazinewith nitrate, and digoxin.

The present disclosure also provides INHBE inhibitors that treat orinhibit a metabolic disorder for use in the treatment of the metabolicdisorder in a subject having: an INHBE variant genomic nucleic acidmolecule encoding a predicted loss-of-function INHBE polypeptide; anINHBE variant mRNA molecule encoding a predicted loss-of-function INHBEpolypeptide; or an INHBE variant cDNA molecule encoding a predictedloss-of-function INHBE polypeptide.

The present disclosure also provides INHBE inhibitors that treat orinhibit a cardiovascular disease for use in the treatment of thecardiovascular disease in a subject having: an INHBE variant genomicnucleic acid molecule encoding a predicted loss-of-function INHBEpolypeptide; an INHBE variant mRNA molecule encoding a predictedloss-of-function INHBE polypeptide; or an INHBE variant cDNA moleculeencoding a predicted loss-of-function INHBE polypeptide.

In some embodiments, the INHBE inhibitor comprises an antisense nucleicacid molecule, a small interfering RNA (siRNA), or a short hairpin RNA(shRNA) that hybridizes to an INHBE mRNA. In some embodiments, the INHBEinhibitor comprises a Cas protein and guide RNA (gRNA) that hybridizesto a gRNA recognition sequence within an INHBE genomic nucleic acidmolecule. In some embodiments, the Cas protein is Cas9 or Cpf1. In someembodiments, the gRNA recognition sequence is located within SEQ IDNO:1. In some embodiments, a Protospacer Adjacent Motif (PAM) sequenceis about 2 to 6 nucleotides downstream of the gRNA recognition sequence.In some embodiments, the gRNA comprises from about 17 to about 23nucleotides. In some embodiments, the gRNA recognition sequencecomprises a nucleotide sequence according to any one of SEQ ID NOs:9-27.

All patent documents, websites, other publications, accession numbersand the like cited above or below are incorporated by reference in theirentirety for all purposes to the same extent as if each individual itemwere specifically and individually indicated to be so incorporated byreference. If different versions of a sequence are associated with anaccession number at different times, the version associated with theaccession number at the effective filing date of this application ismeant. The effective filing date means the earlier of the actual filingdate or filing date of a priority application referring to the accessionnumber if applicable. Likewise, if different versions of a publication,website or the like are published at different times, the version mostrecently published at the effective filing date of the application ismeant unless otherwise indicated. Any feature, step, element,embodiment, or aspect of the present disclosure can be used incombination with any other feature, step, element, embodiment, or aspectunless specifically indicated otherwise. Although the present disclosurehas been described in some detail by way of illustration and example forpurposes of clarity and understanding, it will be apparent that certainchanges and modifications may be practiced within the scope of theappended claims.

The following examples are provided to describe the embodiments ingreater detail. They are intended to illustrate, not to limit, theclaimed embodiments. The following examples provide those of ordinaryskill in the art with a disclosure and description of how the compounds,compositions, articles, devices and/or methods described herein are madeand evaluated, and are intended to be purely exemplary and are notintended to limit the scope of any claims. Efforts have been made toensure accuracy with respect to numbers (such as, for example, amounts,temperature, etc.), but some errors and deviations may be accounted for.Unless indicated otherwise, parts are parts by weight, temperature is in° C. or is at ambient temperature, and pressure is at or nearatmospheric.

EXAMPLES Example 1: Loss of Function in INHBE is Associated with a MoreFavorable Fat Distribution and Protection Against Type 2 Diabetes inHumans

An exome-wide association analysis for fat distribution, measured by thewaist-to-hip circumference ratio adjusted for body mass index(BMI-adjusted WHR), was performed. BMI-adjusted WHR is a measure of bodyfat distribution independent of overall adiposity. For each gene in thegenome, associations with BMI-adjusted WHR for the burden of rarepredicted loss-of-function genetic variants (pLOF variants withalternative allele frequency [AAF]<1%) were estimated. In this analysis,the burden of rare (AAF<1%) predicted loss-of-function (pLOF) variantsin INHBE was associated with a more favorable fat distribution (i.e.,lower WHR adjusted for BMI; see, FIG. 1 and FIG. 2) at the exome-widelevel of statistical significance (p<3.6×10⁻⁷, corresponding to aBonferroni correction for the number of tests). Table 6 shows results ofassociations with fat distribution for pLOF variants in INHBE in 285,605European ancestry participants in the UKB cohort (associations withBMI-adjusted WHR; genetic exposure is the burden of pLOF variants withAAF<1%). INHBE pLOF were strongly associated with lower BMI-adjusted WHR(see, Table 6). This statistically significant association was furtherreplicated in a meta-analysis of additional data including a secondtranche of UKB data (over 140,000 European ancestry participants) andover 95,000 admixed American participants from the MCPS study (see, FIG.1).

TABLE 6 INHBE gene-burden association result for BMI adjusted WHR in theUKB Genotype Per allele beta Per allele effect counts, (95% CI) in BMI(95% CI) in RR|RA|AA adjusted WHR AAF SD units P-value genotypes units0.0012 −0.21 2.80E−08 285,605: −0.02 (−0.29, −0.14) 284,942|663|0(−0.02, −0.01)Abbreviations: UKB=UK biobank study population, AAF=frequency of pLOFalleles across pLOF variants in the gene, RR=count of individuals havingno heterozygous or homozygous observations of pLOFs variants in thegene, RA=count of individuals with at least one heterozygous pLOF and nohomozygotes pLOF variants in the gene, AA=count of individuals with atleast one homozygous pLOF variants in the gene, CI=confidence interval,pLOF=predicted loss-of-function, SD=standard deviation.

Table 6 shows the association of INHBE pLOF with BMI-adjusted WHR in theEuropean ancestry individuals of the UK Biobank study population. Theeffect of INHBE pLOF variants was estimated in standard deviation (SD)units and in the ratio units of WHR. Table 6 shows that INHBE pLOFcarriers have a lower BMI adjusted WHR compared to the average ofindividuals not carrying these genetic variants in analyses adjustingfor covariates, ancestry and relatedness. Genotype counts display thenumber of individuals in the population studies carrying no variantsleading to pLOF of INHBE (RR), one or more variants resulting in pLOF ofa single INHBE allele (RA), or one or more pLOF variants in both INHBEalleles (AA).

This association of INHBE pLOF variants with lower BMI-adjusted WHR wasconsistent in men and women from the UK Biobank cohort (see, Table 7;genetic exposure is the burden of pLOF variants with AAF<1%).

TABLE 7 Sex-stratified INHBE pLOF variants association in the UKB Perallele beta (95% CI) Per allele Genotype in BMI Cohort effect counts,adjusted (Sub- (95% CI) RR|RA|AA waist-hip population) AAF in SD unitsP-value genotypes ratio units UKB 0.001 −0.19 2.8E−06 232,890: −0.01(EUR (−0.27, 232,329|561|0 (−0.02, −0.01) women) −0.11) UKB 0.001 −0.163.6E−04 196,500: −0.01 (EUR men) (−0.25, 196,056|444|0 (−0.01, 0.005)−0.07)Abbreviations: UKB=UK biobank study population, AAF=frequency of pLOFalleles across pLOF variants in the gene, RR=count of individuals havingno heterozygous or homozygous observations of pLOFs variants in thegene, RA=count of individuals with at least one heterozygous pLOF and nohomozygotes pLOF variants in the gene, AA=count of individuals with atleast one homozygous pLOF variants in the gene, CI=confidence interval,pLOF=predicted loss of function, SD=standard deviation.

Table 7 shows the association of INHBE pLOF with BMI-adjusted WHR inEuropean ancestry individuals from the UK Biobank study stratified bysex. The effect of INHBE pLOF variants was estimated in standarddeviation (SD) units and in ratio units of WHR. Genotype counts displaythe number of individuals in the population studies carrying no variantsleading to pLOF of INHBE (RR), one or more variants resulting in pLOF ofa single INHBE allele (RA), or one or more pLOF variants in both INHBEalleles (AA). The association of INHBE pLOF variants with lowerBMI-adjusted WHR was similarly strong in men and women included in thisanalysis.

Among pLOF variants in INHBE, the variant with the strongest associationwith BMI-adjusted WHR was a c.299-1G>C (12:57456093:G:C according toGRCh38/hg38 human genome assembly coordinates) mutation, predicted toaffect the intron 1 acceptor splice site shortening exon 2 by 12nucleotides at the 5′ end (see, FIG. 3 and Table 8) and result in anin-frame deletion within the pro-domain of the INHBE protein (see, FIG.4).

TABLE 8 Effect on splicing for the 12:57456093:G:C acceptor splice-sitevariant as predicted by the SpliceAI software. VARIANT SPLICE CHANGEDELTA SCORE 12:57456093:G:C Acceptor loss 0.98 Acceptor gain 0.9 Deltascore: Value between 0-1, interpreted as the probability of the varianthaving a splice-change effect on the INHBE gene.

Table 8 shows the predicted effect of the variant 12:57456093:G:C onsplicing of the INHBE gene.

In Chinese hamster ovary (CHO) cells, the c.299-1G>C splice variant wasexpressed and was found to result in a lower molecular weight proteinthat is not secreted outside the cell, indicating a loss-of-function(see, FIG. 5).

pLOF variants in INHBE were associated with larger hip circumference,higher arm and leg fat mass, suggestive of greater ability to storecalories in peripheral adipose tissue (see, FIG. 6 and Table 9).

TABLE 9 Association of pLOF genetic variants in INHBE with adiposityphenotypes meta-analyzed across the UKB, Geisinger Health System (GHS)and MCPS studies Per allele Per allele Genotype beta Outcome effectcounts (95% CI) (Clinical Genetic (95% CI) RR|RA|AA in clinical Units)exposure in SD units P-value genotypes units BMI INHBE 0.06 0.02645,626: 0.33 (kg/m²) pLOF; (0.01, 644,402|1,224|0 (0.04, AAF <1% 0.11)0.61) Waist −0.03 0.26 526,076: −0.45 (cm) (−0.09, 525,034|1,042|0(−1.22, 0.03) 0.33) Hip (cm) 0.07 0.03 526,031: 0.63 (0.01,524,989|1,042|0 (0.08, 0.13) 1.19)Abbreviations: UKB=UK biobank study population, GHS=Geisinger HealthSystem study population, MCPS=Mexico City Prospective Study population,AAF=frequency of pLOF alleles across pLOF variants in the gene, RR=countof individuals having no heterozygous or homozygous observations ofpLOFs variants in the gene, RA=count of individuals with at least oneheterozygous pLOF and no homozygotes pLOF variants in the gene, AA=countof individuals with at least one homozygous pLOF variants in the gene,CI=confidence interval, pLOF=predicted loss-of-function, SD=standarddeviation, kg/m²=kilograms per meter square, cm=centimeters. Genotypecounts display the number of individuals in the population studiescarrying no variants leading to pLOF of INHBE (RR), one or more variantsresulting in pLOF of a single INHBE allele (RA), or one or more pLOFvariants in both INHBE alleles (AA).

Table 9 shows the association of INHBE pLOF with BMI, waistcircumference, and hip circumference. The effect of INHBE pLOF isquantified in units of standard deviation, or in the respective clinicalunits of each anthropometric variable.

Rare pLOF variants in INHBE were also associated with protection againsttype 2 diabetes in humans. It was also found that INHBE pLOF variantswere associated with lower risk of type 2 diabetes (T2D) (see, Table 10;genetic exposure is the burden of pLOF variants with AAF<1%),constituting the first evidence linking LOF in INHBE with type 2diabetes in humans.

TABLE 10 Association of pLOF genetic variants in INHBE with T2D in theUKB, GHS and MCPS studies Genotype Genotype counts counts Per alleleRR|RA|AA RR|RA|AA OR genotypes genotypes Cohort AAF (95% CI) P-value(cases) (controls) UKB 0.001  0.82 0.15    23,907: 402,934: (0.62, 1.08)23,862|45|0 401,981|953|0 GHS 0.001  0.44 0.0006  25,846: 63,749: (0.28,0.70) 25,828|18|0 63,639|110|0 MCPS 0.0002 0.38 0.08    13,739: 83,278:(0.13, 1.11) 13,738|1|0 83,243|35|0 Meta- 0.001  0.68 0.00097 63,492:549,961: analysis (0.54, 0.85) 63,428|64|0 548,863|1,098|0Abbreviations: Meta-analysis=Joint analysis of all listed studypopulations, AAF=frequency of pLOF alleles across pLOF variants in thegene, RR=count of individuals having no heterozygous or homozygousobservations of pLOFs variants in the gene, RA=count of individuals withat least one heterozygous pLOF and no homozygotes pLOF variants in thegene, AA=count of individuals with at least one homozygous pLOF variantsin the gene, CI=confidence interval, pLOF=predicted loss-of-function,SD=standard deviation. Genotype counts display the number of individualsin the population studies either being cases of T2D or not in the T2Dcategory carrying no variants leading to pLOF of INHBE (RR), one or morevariants resulting in pLOF of a single INHBE allele (RA), or one or morepLOF variants in both INHBE alleles (AA).

Table 10 shows the association with T2D for pLOF variants in INHBE froman analysis of the UK Biobank (UKB), Geisinger Health System (GHS), andMexico City Prospective study (MCPS) populations. The results show that,within each study population, INHBE pLOF variants were associated withlower risk of T2D and this was confirmed in a meta-analysis whichcombines results across all three study populations.

Furthermore, INHBE pLOF variants were associated with a favorablemetabolic profile in an analysis across multiple cohorts (see, Table 11;genetic exposure is the burden of INHBE pLOF variants with AAF<1%),including lower HbA1c, ALT, triglycerides and LDL-C and higher HDL-C.

TABLE 11 Association of pLOF genetic variants in INHBE with metabolicmeta-analyzed across the UKB, GHS and MCPS studies Per allele Per allelebeta effect Genotype (95% CI) Outcome (95% CI) counts in (Clinical in SDRR|RA|AA Clinical Units) AAF units P-value genotypes Units Glucose 0.0010.04 0.24    460,195|1,023|0 0.76 (mg/dL) (−0.02, (−0.51, 0.10) 2.03)HbA1c 0.001 −0.06 0.038   574,104|1,086|0 −0.05 (%) (−0.11, (−0.10,−0.003) −0.003) AST 0.001 0.0028 0.92    514,592|1,122|0 0.03 (U/L)(−0.05, (−0.5, 0.06) 0.6) ALT 0.001 −0.07 0.014   517,194|1,123|0 −1.0(U/L) (−0.13, (−1.7, −0.01) −0.2) Tri- 0.001 −0.11 0.00017500,594|1,092|0 −9.2 glycerides (−0.16, (−14.1, (mg/dL) −0.05) −4.4)HDL-C 0.001 0.13 3.1 × 10⁻⁰⁶ 466,201|1,024|0 2.0 (mg/dL) (0.08, (1.1,0.19) 2.8) LDL-C 0.001 −0.06 0.04    499,334|1,092|0 −1.9 (mg/dL)(−0.11, (−3.7, −0.003) −0.1)Abbreviations: UKB=UK biobank study population, GHS=Geisinger HealthSystem study population, MCPS=Mexico City Prospective Study,AAF=frequency of pLOF alleles across pLOF variants in the gene, RR=countof individuals having no heterozygous or homozygous observations ofpLOFs variants in the gene, RA=count of individuals with at least oneheterozygous pLOF and no homozygotes pLOF variants in the gene, AA=countof individuals with at least one homozygous pLOF variants in the gene,CI=confidence interval, pLOF=predicted loss-of-function, SD=standarddeviation, mg/dL=milligrams per deciliter, U/L=Units per liter. Genotypecounts display the number of individuals in the population studiescarrying no variants leading to pLOF of INHBE (RR), one or more variantsresulting in pLOF of a single INHBE allele (RA), or one or more pLOFvariants in both INHBE alleles (AA).

Table 11 shows the association of INHBE pLOF variants with a range ofmetabolic phenotypes as estimated in a meta-analysis of the UKB, GHS,and MCPS study populations. Results are shown both in units of standarddeviation, and in the original clinical units of the relevant metabolicphenotype.

In addition, INHBE pLOF variants were associated with reduced liverinflammation indices at magnetic resonance imaging (see, Table 12;genetic exposure is the burden of INHBE pLOF variants with AAF<1%).

TABLE 12 Association of pLOF genetic variants in INHBE with liverimaging phenotypes in the UKB Outcome Effect (95% Cl) Effect (95% Cl)Allele count ALT allele (Clinical Units) in SD units in Clinical unitsP-value cases AAF carriers % ECF −0.25 −0.012 0.026 36,690|70|0 0.000950.19% (Fraction of (−0.47,−0.03) (−0.029, −0.002) sampled pixels) ECFadjusted^(a) −0.29 −0.018 0.0060 35,205|69|0 0.00098 0.20% (Fraction of(−0.50, −0.08) (−0.031, −0.005) sampled pixels) PDFF 0.06 0.29 0.56036,690|70|0 0.00095 0.19% (Fraction of (−0.15, 0.27) (−0.72, 1.31)sampled pixels) PDFF adjusted^(a) 0.05 0.24 0.569 35,205|69|0 0.000980.20% (Fraction of (−0.12, 0.22) (−0.58, 1.06) sampled pixels) cT1 −0.23−10.4 0.047 36,690|70|0 0.00095 0.19% (time in (−0.45, −0.00) (−21.3,−0.00) milliseconds) cT1 adjusted^(a) −0.26 −11.83 0.012 35,205|69|00.00098 0.20% (time in (−0.47, −0.06) (−21.38, −2.73) milliseconds) T1−0.33 −15.3 0.0035 36,690|70|0 0.00095 0.19% (time in (−0.56, −0.11)(−25.95, −5.10) milliseconds) T1 adjusted^(a) −0.36 −16.68 0.0009735,205|69|0 0.00098 0.20% (time in (−0.57, −0.14) (−26.41, −6.49)milliseconds) ^(a)Adjusted for technical covariates including BMI,alcohol usage, and diabetes.Abbreviations: PDFF=Proton density fat fraction (defined as the ratio ofdensity of mobile protons from fat (triglycerides) and the total densityof protons from mobile triglycerides and mobile water and reflects theconcentration of fat within a tissue), ECF=extracellular fluid, T1=timeconstant for recovery of longitudinal magnetization. It's a relaxationtime which measures how quickly the net magnetization recovers to itsground state. It can differ significantly based on the strength of themagnetic field and based on tissue composition. Furthermore, itincreases with increased magnetic field, while it decreases withpresence of fat and/or iron in the tissue, cT1=T1 corrected for theeffects of liver iron content which result in T1 values beingunderestimated, UKB=UK biobank study population, AAF=frequency of pLOFalleles across pLOF variants in the gene, RR=count of individuals havingno heterozygous or homozygous observations of pLOFs variants in thegene, RA=count of individuals with at least one heterozygous pLOF and nohomozygotes pLOF variants in the gene, AA=count of individuals with atleast one homozygous pLOF variants in the gene, CI=confidence interval,pLOF=predicted loss-of-function, SD=standard deviation.

Table 12 shows the association of INHBE pLOF variants with a range ofliver imaging phenotypes in European ancestry individuals from the UKBiobank study population. The results show that INHBE pLOF variants areassociated with lower levels of ECF and cT1 which are measures of liverinflammation, as defined by magnetic resonance imaging.

It was additionally investigated whether INHBE pLOF variants wereassociated with liver histopathology phenotypes in 3,565 bariatricsurgery patients from the GHS cohort who underwent exome sequencing anda perioperative wedge biopsy of the liver. There were only threecarriers for pLOF variants in INHBE in that set, but carrier status wasassociated with lower nonalcoholic fatty liver disease activity score(see, Table 13), a measure of the severity of liver disease at biopsythat sums steatosis, lobular inflammation and ballooning grades (Kleineret al., Hepatology, 2005, 41, 1313-21).

TABLE 13 Association with lower nonalcoholic fatty liver diseaseactivity score for rare pLOF variants in INHBE Beta in SD of NAFLDactivity score per allele INHBE pLOF genotypes Outcome (95% CI) P-value(Ref/Het/Hom) NAFLD activity −1.05 0.026 3,565|3|0 score (−1.98, −0.12)The association with NAFLD activity score (outcome) for rare pLOFvariants in INHBE was reported. The association was estimated in 3,565bariatric surgery patients from GHS.

Finally, it was found that a common variant near INHBE (12:57259799:A:C;r57966846; AAF, 0.28) is associated with higher liver expression levelsof INHBE mRNA (per-allele beta, 0.3 SDs of INHBE transcript abundance asquantified by RNASeq in over 2,000 participants to GHS who underwent aliver biopsy as part of bariatric surgery). It was also found that the12:57259799:A:C variant is associated with higher BMI-adjusted WHR,triglycerides and risk of type 2 diabetes. The expression raising alleleC was associated with higher BMI-adjusted WHR (p-value=1.5×10⁻⁴), highertriglycerides (p-value=2.0×10⁻¹¹), higher T2D risk (p-value=0.03) (see,Table 14). This shows that genetically-determined overexpression ofINHBE is associated with higher metabolic disease risk, while a loss offunction is associated favorable metabolic profile and lower diabetesrisk (as noted above from the pLOF variants associations).

TABLE 14 Association of an INHBE eQTL, 12:57259799:A:C, with variousmetabolic phenotypes in the UKB and GHS cohorts Per allele effect (95%Cl) Per allele beta Genetic Outcome in SD units (95% Cl) in Genotypecounts, exposure (Clinical Units) AAF or odds ratio Clinical UnitsP-value RR|RA|AA genotypes 12:57259799: Triglycerides 0.285 0.01 SDs 0.92.0 × 10⁻¹¹ 274,658|216,943| A:C, (mg/dL) (0.009, 0.02) (0.9, 1.0)43,388 Count of BMI-adj 0.285 0.008 SDs 0.00064 1.5 × 10⁻⁴235,613|187,407| INHBE liver WHR (0.004, 0.012) (0.00032, 37,740expression (ratio units) 0.00080) raising T2D 0.285 1.02^(a) — 0.037 T2DControls: allele C (1.00^(a), 1.04^(a)) 255,408|201,524| 40,210 T2DCases: 27,105|21,053|4,295 ^(a)Estimates are in odds ratios.Abbreviations: AAF=allele frequency of INHBE liver expression raisingallele (i.e., alternate allele), CI=confidence interval, SD=standarddeviation, RR=reference-reference allele, RA=reference-alternativeallele, AA=alternative-alternative allele, mg/dL=milligrams perdeciliter. Genotype counts display the number of individuals in thepopulation studies having no copies of the INHBE liver expressionraising allele (RR), having only one copy of the INHBE liver expressionraising allele (RA), and having 2 copies of the INHBE liver expressionraising allele (AA). Genotype counts are further stratified withinindividuals classified as T2D cases in the study population.

The association of 12:57259799:A:C with triglyceride levels, WHRadjBMI,and T2D risk was studied in all European ancestry participants from theUK Biobank and Geisinger Health studies. The results show that12:57259799:A:C was significantly associated with higher triglyceridelevels and higher BMI-adjusted WHR; in addition, there was anassociation with higher T2D risk.

Example 2: INHBE is Highly Expressed in Human Hepatocytes and itsExpression was Upregulated in Patients with Steatosis and NonalcoholicSteatohepatitis

The mRNA expression of INHBE across tissues in humans from the GenotypeTissue Expression consortium (GTEx) was examined and it was found thatINHBE is most highly expressed in liver among the GTEx tissues (see,FIG. 7). The mRNA expression of INHBE among cell types was also examinedin data from the Human Protein Atlas (HPA) and it was found that INHBEwas most highly expressed in hepatocytes (see, FIG. 7). The level ofexpression of INHBE in the liver of over 2,000 bariatric surgerypatients in GHS who underwent liver RNASeq was also estimated. It wasdiscovered that INHBE expression was upregulated in patients withsteatosis of the liver compared to individuals with normal liver, inpatients with nonalcoholic steatohepatitis compared to individuals withnormal liver, and in patients with nonalcoholic steatohepatitis comparedto patients with steatosis (see, FIG. 8).

Example 3: Associations with Visceral to Gluteofemoral Fat Ratio asMeasured by MRI for INHBE Identified in the BMI-Adjusted WHR DiscoveryAnalysis

A subset of approximately 46,000 participants in UKB underwent two-pointDixon (Dixon, Radiology, 1984, 153, 189-194) MRI using Siemens MAGNETOMAera 1.5T clinical MRI scanners (Littlejohns et al., Nat. Commun., 2020,11, 2624), split into six different imaging series. This subset included38,880 people with available exome sequencing. Stitching of the sixdifferent scan positions corrected for overlapping slices, partialscans, repeat scans, fat-water swaps, misalignment between imagingseries, bias-field, artificially dark slices and local hotspots, similarto what has previously been performed (Basty et al., Image Processingand Quality Control for Abdominal Magnetic Resonance Imaging in the UKBiobank, 2020, ArXiv abs/2007.01251). A total of 52 subjects had theirwhole-body Dixon MRI manually annotated into six different classes offat: upper body fat, abdominal fat, visceral fat, mediastinal fat,gluteofemoral fat and lower-leg fat. Special care was taken to tailorthe training dataset to attempt to span the phenotypic diversityexpected by specifically including training subjects that have geneticmutations that predispose them to abnormal fat and muscle phenotypessuch as PPARG (Ludtke et al., J. Med. Genet., 2007, 44, e88), PLIN1(Gandotra et al., N. Engl. J. Med., 2011, 364, 740-748), LMNA (Jeru etal., J. Med. Genet., 2017, 54, 413-416), LIPE (Zolotov et al., Am. J.Med. Genet., 2017, A 173, 190-194) and MC4R (Akbari et al., Science,2021, 373). These annotations were then used to train a multi-classsegmentation deep neural-net which employed a UNet (Weng et al., IEEEAccess, 2021, 9, 16591-16603) architecture with a ResNet34 (He et al.,in 2016 IEEE Conference on Computer Vision and Pattern Recognition(CVPR), 2016, 770-778) backbone, and a loss function of a sum of theJaccard Index and categorical focal loss (Lin et al., IEEE Transactionson Pattern Analysis and Machine Intelligence, 2020, 42, 318-327). Fatvolume phenotypes were calculated by summing the resulting segmentationmaps from the neural net for each corresponding fat class. Thevisceral-to-gluteofemoral fat ratio was then calculated as the ratio ofvisceral to gluteofemoral fat volume for a given individual.

Rare coding variants in INHBE associated with BMI-adjusted WHR showedhighly consistent associations with visceral-to-gluteofemoral fat ratioat MRI, a refined measure of fat distribution, in a subset of 38,880people (i.e., ˜6% of the discovery sample) who had undergone awhole-body MRI in UKB (see, Table 15). There was a nominally-significantassociation with lower MRI-defined visceral-to-gluteofemoral fat ratiofor INHBE pLOF variants in the subset of UKB with MRI data (beta in SDunits of fat ratio per allele, −0.24; 95% CI, −0.45 to −0.02; p=0.03;see, Table 15).

TABLE 15 Beta (95% CI) per allele in SD Genotype counts, AAF, units ofvisceral to gluteofemoral RR|RA|AA fraction fat ratio from MRI Pgenotypes of 1 −0.238 3.0E−02 38802|78|0 0.0010 (−0.453, −0.023)Each gene-burden result in the table was analyzed in a model thataccounted for the sex specific effects of age, body mass index, andheight on visceral to gluteofemoral fat ratio. Abbreviations: pLOF,predicted loss of function; AAF, alternative allele frequency; CI,confidence intervals; SD, standard deviation; BMI, body mass index; p,P-value; RR, reference homozygote genotype; RA, reference-alternativegenotype; AA, alternative homozygote genotype.

Example 4: INHBE Predicted Loss-of-Function Association with IncreasedLeft Ventricular Ejection Fraction and Protection of Cardiomyopathy

Cases in the present example were any study participant without heartdisease. The results were based on meta-analyses of UKB, GHS, SINAI,UPENN-PMBB, MDCS, Indiana-Chalasani. Predicted loss-of-function in INHBEassociated with increased left ventricular ejection fraction andprotection of cardiomyopathy are shown in Table 16 (Burden of INHBE rarepLoF variants (M1.1)).

TABLE 16 Beta_(SD) or Clin. Case allele Control allele Outcome OR [95%Cl] unit P-value count (RR|RA|AA) count (RR|RA|AA) AA carriers 1 0.261.57% 0.019 38,651|80|0 — 0.21% (0.04, 0.47) 2 0.46 — 0.034 5,111|2|0342,838|650|0 0.19% (0.23, 0.95) Outcome 1 is left ventricular ejectionfraction*. Outcome 2 is non-ischemic cardiomyopathy**. *Left ventricularejection fraction obtained by cardiac MRI in participants of the UKBiobank. **Non-ischemic cardiomyopathy cases were defined as studyparticipants with one or more of the following ICD10 codes: I420(Dilated Cardiomyopathy), I425 (Other restrictive cardiomyopathy), I428(Other noncompaction cardiomyopathies), I429 (primarycardiomyopathy|unspecified), and absence of one or more of any ICD10code indicative of myocardial infarction (I21|I22|I23|I252|I256) andhypertrophic cardiomyopathy (I421, I422).

Association of pLOF variants with lower blood pressure (see, Table 17;burden of INHBE rare pLOF variants—M1.1) is consistent with beneficialeffect on hemodynamic traits.

TABLE 17 Beta Effect in (95% CI) mmHg AAF, Genotype per allele (95% CI)fraction Counts Trait in SD units per allele P-value of 1 (RR|RA|AA) 1−0.06 −0.56 0.03 0.00102 599,306|1,224|0 (−0.11, (−1.07, −0.01) −0.05) 2−0.05 −0.84 0.0614 0.00102 599,608|1,224|0 (−0.10, (−1.72, 0.00) 0.04)Trait 1 is diastolic blood pressure (treatment corrected). Trait 2 issystolic blood pressure (treatment corrected).

Various modifications of the described subject matter, in addition tothose described herein, will be apparent to those skilled in the artfrom the foregoing description. Such modifications are also intended tofall within the scope of the appended claims. Each reference (including,but not limited to, journal articles, U.S. and non-U.S. patents, patentapplication publications, international patent application publications,gene bank accession numbers, and the like) cited in the presentapplication is incorporated herein by reference in its entirety and forall purposes.

1-160. (canceled)
 161. A method of treating a subject with a therapeuticagent that treats or inhibits a metabolic disorder, wherein the subjectis suffering from a metabolic disorder, the method comprising the stepsof: determining whether the subject has an Inhibin Subunit Beta E(INHBE) variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide by: obtaining or having obtained abiological sample from the subject; and performing or having performed agenotyping assay on the biological sample to determine if the subjecthas a genotype comprising the INHBE variant nucleic acid molecule; andwhen the subject is INHBE reference, then administering or continuing toadminister to the subject the therapeutic agent that treats or inhibitsthe metabolic disorder in a standard dosage amount, and/or administeringto the subject an INHBE inhibitor; and when the subject is heterozygousfor an INHBE variant nucleic acid molecule, then administering orcontinuing to administer to the subject the therapeutic agent thattreats or inhibits the metabolic disorder in an amount that is the sameas or lower than a standard dosage amount, and/or administering to thesubject an INHBE inhibitor; when the subject is homozygous for an INHBEvariant nucleic acid molecule, then administering or continuing toadminister to the subject the therapeutic agent that treats or inhibitsthe metabolic disorder in an amount that is the same as or lower than astandard dosage amount; wherein the presence of a genotype having theINHBE variant nucleic acid molecule encoding an INHBE predictedloss-of-function polypeptide indicates the subject has a decreased riskof developing the metabolic disorder.
 162. The method according to claim161, wherein the subject is INHBE reference, and the subject isadministered or continued to be administered the therapeutic agent thattreats or inhibits the metabolic disorder in a standard dosage amount,and/or is administered an INHBE inhibitor.
 163. The method according toclaim 161, wherein the subject is heterozygous for an INHBE variantnucleic acid molecule, and the subject is administered or continued tobe administered the therapeutic agent that treats or inhibits themetabolic disorder in an amount that is the same as or lower than astandard dosage amount, and/or is administered an INHBE inhibitor. 164.The method according to claim 161, wherein the INHBE variant nucleicacid molecule is a missense variant, a splice-site variant, a stop-gainvariant, a start-loss variant, a stop-loss variant, a frameshiftvariant, or an in-frame indel variant, or a variant that encodes atruncated INHBE polypeptide.
 165. The method according to claim 161,wherein the INHBE inhibitor comprises an antisense nucleic acid moleculethat hybridizes to an INHBE mRNA.
 166. The method according to claim161, wherein the INHBE inhibitor comprises an siRNA that hybridizes toan INHBE mRNA.
 167. The method according to claim 161, wherein the INHBEinhibitor comprises an shRNA that hybridizes to an INHBE mRNA.
 168. Themethod according to claim 161, wherein the metabolic disorder is type 2diabetes, and the therapeutic agent is chosen from metformin, insulin,glyburide, glipizide, glimepiride, repaglinide, nateglinide,thiazolidinediones, rosiglitazone, pioglitazone, sitagliptin,saxagliptin, linagliptin, exenatide, liraglutide, semaglutide,canagliflozin, dapagliflozin, and empagliflozin, or any combinationthereof.
 169. The method according to claim 161, wherein the metabolicdisorder is obesity, and the therapeutic agent is chosen from orlistat,phentermine, topiramate, bupropion, naltrexone, and liraglutide, or anycombination thereof.
 170. The method according to claim 161, wherein themetabolic disorder is elevated triglyceride, and the therapeutic agentis chosen from rosuvastatin, simvastatin, atorvastatin, fenofibrate,gemfibrozil, fenofibric acid, niacin, and an omega-3 fatty acid, or anycombination thereof.
 171. The method according to claim 161, wherein themetabolic disorder is lipodystrophy, and the therapeutic agent is chosenfrom tesamorelin, metformin, poly-L-lactic acid, calcium hydroxyapatite,polymethylmethacrylate, bovine collagens, human collagens, silicone, andhyaluronic acid, or any combination thereof.
 172. The method accordingto claim 161, wherein the metabolic disorder is liver inflammation, andthe therapeutic agent is a hepatitis therapeutic or a hepatitis vaccine.173. The method according to claim 161, wherein the metabolic disorderis fatty liver disease include, and the subject is administeredbariatric surgery and/or dietary intervention.
 174. The method accordingto claim 161, wherein the metabolic disorder is hypercholesterolemia,and the therapeutic agent is chosen from: atorvastatin, fluvastatin,lovastatin, pitavastatin, pravastatin, rosuvastatin calcium,simvastatin, cholestyramine, colesevelam, and colestipol, alirocumab,evolocumab, niaspan, niacor, fenofibrate, gemfibrozil, and bempedoic, orany combination thereof.
 175. The method according to claim 161, whereinthe metabolic disorder is an elevated liver enzyme), and the therapeuticagent is chosen from coffee, folic acid, potassium, vitamin B6, astatin, and fiber, or any combination thereof.
 176. The method accordingto claim 161, wherein the metabolic disorder is nonalcoholicsteatohepatitis (NASH) and the therapeutic agent is obeticholic acid,Selonsertib, Elafibranor, Cenicriviroc, GR_MD_02, MGL_3196, IMM124E,arachidyl amido cholanoic acid, GS0976, Emricasan, Volixibat, NGM282,GS9674, Tropifexor, MN_001, LMB763, BI_1467335, MSDC_0602, PF_05221304,DF102, Saroglitazar, BMS986036, Lanifibranor, Semaglutide, Nitazoxanide,GRI_0621, EYP001, VK2809, Nalmefene, LIK066, MT_3995, Elobixibat,Namodenoson, Foralumab, SAR425899, Sotagliflozin, EDP 305, Isosabutate,Gemcabene, TERN_101, KBP_042, PF_06865571, DUR928, PF_06835919, NGM313,BMS_986171, Namacizumab, CER_209, ND_L02_s0201, RTU_1096, DRX_065,IONIS_DGAT2Rx, INT_767, NC_001, Seladepar, PXL770, TERN_201, NV556,AZD2693, SP_1373, VK0214, Hepastem, TGFTX4, RLBN1127, GKT_137831,RYI_018, CB4209-CB4211, and JH_0920.
 177. A method of treating a subjectwith a therapeutic agent that treats or inhibits a cardiovasculardisease, wherein the subject is suffering from a cardiovascular disease,the method comprising the steps of: determining whether the subject hasan Inhibin Subunit Beta E (INHBE) variant nucleic acid molecule encodingan INHBE predicted loss-of-function polypeptide by: obtaining or havingobtained a biological sample from the subject; and performing or havingperformed a genotyping assay on the biological sample to determine ifthe subject has a genotype comprising the INHBE variant nucleic acidmolecule; and when the subject is INHBE reference, then administering orcontinuing to administer to the subject the therapeutic agent thattreats or inhibits the cardiovascular disease in a standard dosageamount, and/or administering to the subject an INHBE inhibitor; and whenthe subject is heterozygous for an INHBE variant nucleic acid molecule,then administering or continuing to administer to the subject thetherapeutic agent that treats or inhibits the cardiovascular disease inan amount that is the same as or lower than a standard dosage amount,and/or administering to the subject an INHBE inhibitor; when the subjectis homozygous for an INHBE variant nucleic acid molecule, thenadministering or continuing to administer to the subject the therapeuticagent that treats or inhibits the cardiovascular disease in an amountthat is the same as or lower than a standard dosage amount; wherein thepresence of a genotype having the INHBE variant nucleic acid moleculeencoding an INHBE predicted loss-of-function polypeptide indicates thesubject has a decreased risk of developing the cardiovascular disease.178. The method according to claim 177, wherein the subject is INHBEreference, and the subject is administered or continued to beadministered the therapeutic agent that treats or inhibits thecardiovascular disease in a standard dosage amount, and/or isadministered an INHBE inhibitor.
 179. The method according to claim 177,wherein the subject is heterozygous for an INHBE variant nucleic acidmolecule, and the subject is administered or continued to beadministered the therapeutic agent that treats or inhibits thecardiovascular disease in an amount that is the same as or lower than astandard dosage amount, and/or is administered an INHBE inhibitor. 180.The method according to claim 177, wherein the INHBE variant nucleicacid molecule is a missense variant, a splice-site variant, a stop-gainvariant, a start-loss variant, a stop-loss variant, a frameshiftvariant, or an in-frame indel variant, or a variant that encodes atruncated INHBE polypeptide.
 181. The method according to claim 177,wherein the INHBE inhibitor comprises an antisense nucleic acid moleculethat hybridizes to an INHBE mRNA.
 182. The method according to claim177, wherein the INHBE inhibitor comprises an siRNA that hybridizes toan INHBE mRNA.
 183. The method according to claim 177, wherein the INHBEinhibitor comprises an shRNA that hybridizes to an INHBE mRNA.
 184. Themethod according to claim 177, wherein the cardiovascular disease ishigh blood pressure, and the therapeutic agent is chosen fromchlorthalidone, chlorothiazide, hydrochlorothiazide, indapamide,metolazone, acebutolol, atenolol, betaxolol, bisoprolol fumarate,carteolol hydrochloride, metoprolol tartrate, metoprolol succinate,nadolol, benazepril hydrochloride, captopril, enalapril maleate,fosinopril sodium, lisinopril, moexipril, perindopril, quinaprilhydrochloride, ramipril, trandolapril, candesartan, eprosartan mesylate,irbesartan, losartan potassium, telmisartan, valsartan, amlodipinebesylate, bepridil, diltiazem hydrochloride, felodipine, isradipine,nicardipine, nifedipine, nisoldipine, verapamil hydrochloride, doxazosinmesylate, prazosin hydrochloride, terazosin hydrochloride, methyldopa,carvedilol labetalol hydrochloride, alpha methyldopa, clonidinehydrochloride, guanabenz acetate, guanfacine hydrochloride, guanadrel,guanethidine monosulfate, reserpine, hydralazine hydrochloride, andminoxidil, or any combination thereof.
 185. The method according toclaim 177, wherein the cardiovascular disease is cardiomyopathy, and thetherapeutic agent is an ACE inhibitor, an angiotensin II receptorblocker, a beta blocker, a calcium channel blocker, digoxin, anantiarrhythmic, an aldosterone blocker, a diuretic, an anticoagulant, ablood thinner, and a corticosteroid.
 186. The method according to claim177, wherein the cardiovascular disease is heart failure, and thetherapeutic agent is an ACE inhibitor, an angiotensin-2 receptorblocker, a beta blocker, a mineralocorticoid receptor antagonist, adiuretic, ivabradine, sacubitril valsartan, hydralazine with nitrate,and digoxin.